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The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (
DNA replication In , DNA replication is the of producing two identical replicas of DNA from one original molecule. DNA replication occurs in all acting as the most essential part for . This is essential for cell division during growth and repair of damaged tis ...

DNA replication
) and some of its
organelles In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, ...
, and subsequently the partitioning of its cytoplasm and other components into two daughter cells in a process called
cell division Cell division is the process by which a parent cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or religiou ...

cell division
. In cells with nuclei (
eukaryotes Eukaryotes () are organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contiguous system that embodies the Life#Biology, properties of life. It is a synonym for "Outline ...
), (i.e.,
animal Animals (also called Metazoa) are multicellular A multicellular organism is an organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms are composed of cells ...

animal
,
plant Plants are predominantly photosynthetic Photosynthesis is a process used by plants and other organisms to Energy transformation, convert light energy into chemical energy that, through cellular respiration, can later be released to fuel ...

plant
,
fungal A fungus (plural The plural (sometimes list of glossing abbreviations, abbreviated ), in many languages, is one of the values of the grammatical number, grammatical category of number. The plural of a noun typically denotes a quantity great ...
, and
protist A protist () is any (that is, an organism whose contain a ) that is not an , , or . While it is likely that protists share a (the ), the exclusion of other eukaryotes means that protists do not form a natural group, or . Therefore, some pro ...
cells), the cell cycle is divided into two main stages:
interphase Interphase is the portion of the cell cycle that is not accompanied by gross changes under the microscope, and includes the G1, S and G2 phases. During interphase, the cell grows (G1), replicates its DNA (S) and prepares for mitosis (G2). A cel ...

interphase
and the
mitotic In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In gene ...

mitotic
(M) phase (including
mitosis In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proce ...

mitosis
and
cytokinesis Cytokinesis () is the part of the cell division biological process, process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of Mitosis, nuclear di ...

cytokinesis
). During interphase, the cell grows, accumulating nutrients needed for mitosis, and replicates its DNA and some of its organelles. During the mitotic phase, the replicated chromosomes, organelles, and cytoplasm separate into two new daughter cells. To ensure the proper replication of cellular components and division, there are control mechanisms known as
cell cycle checkpoint Cell cycle checkpoints are control mechanisms in the Eukaryote, eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are ass ...
s after each of the key steps of the cycle that determine if the cell can progress to the next phase. In cells without nuclei (
prokaryotes A prokaryote () is a single-celled organism A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contig ...

prokaryotes
), (i.e.,
bacteria Bacteria (; common noun bacteria, singular bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typ ...

bacteria
and
archaea Archaea ( ; singular archaeon ) constitute a domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a pa ...

archaea
), the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, ...
is divided into the B, C, and D periods. The B period extends from the end of cell division to the beginning of DNA replication. DNA replication occurs during the C period. The D period refers to the stage between the end of DNA replication and the splitting of the bacterial cell into two daughter cells. The cell-division cycle is a vital process by which a single-celled
fertilized egg A zygote (from Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country located in Southeast Europe. Its population is approximately 10.7 mi ...

fertilized egg
develops into a mature organism, as well as the process by which
hair Hair is a protein filament In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Ph ...

hair
,
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have differ ...

skin
,
blood cell A blood cell, also called a hematopoietic cell, hemocyte, or hematocyte, is a cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or ...

blood cell
s, and some
internal organs An organ is a group of Tissue (biology), tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's tissues can be broadly categorized as parenchyma, the tissue peculiar to (or ...
are renewed. After cell division, each of the daughter cells begin the
interphase Interphase is the portion of the cell cycle that is not accompanied by gross changes under the microscope, and includes the G1, S and G2 phases. During interphase, the cell grows (G1), replicates its DNA (S) and prepares for mitosis (G2). A cel ...

interphase
of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of the cell division.


Phases

The eukaryotic cell cycle consists of four distinct phases: G1 phase,
S phase S phase (Synthesis Phase) is the phase of the cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may ...
(synthesis), G2 phase (collectively known as
interphase Interphase is the portion of the cell cycle that is not accompanied by gross changes under the microscope, and includes the G1, S and G2 phases. During interphase, the cell grows (G1), replicates its DNA (S) and prepares for mitosis (G2). A cel ...

interphase
) and
M phase The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication In , DNA replication is the of pro ...

M phase
(mitosis and cytokinesis). M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's nucleus divides, and
cytokinesis Cytokinesis () is the part of the cell division biological process, process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of Mitosis, nuclear di ...

cytokinesis
, in which the cell's
cytoplasm In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes ...
divides forming two daughter cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase. After cell division, each of the daughter cells begin the
interphase Interphase is the portion of the cell cycle that is not accompanied by gross changes under the microscope, and includes the G1, S and G2 phases. During interphase, the cell grows (G1), replicates its DNA (S) and prepares for mitosis (G2). A cel ...

interphase
of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.


G0 phase (quiescence)

G0 is a resting phase where the cell has left the cycle and has stopped dividing. The cell cycle starts with this phase. Non-proliferative (non-dividing) cells in multicellular
eukaryote Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...

eukaryote
s generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for
neuron A neuron or nerve cell is an electrically excitable cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or re ...

neuron
s). This is very common for cells that are fully differentiated. Some cells enter the G0 phase semi-permanently and are considered post-mitotic, e.g., some liver, kidney, and stomach cells. Many cells do not enter G0 and continue to divide throughout an organism's life, e.g., epithelial cells. The word "post-mitotic" is sometimes used to refer to both quiescent and
senescent Ann Pouder (8 April 1807 – 10 July 1917) photographed on her 110th birthday. A heavily lined face is common in human senescence. Senescence () or biological aging is the gradual deterioration of Function (biology), functional characteristics. ...

senescent
cells. Cellular senescence occurs in response to DNA damage and external stress and usually constitutes an arrest in G1. Cellular senescence may make a cell's progeny nonviable; it is often a biochemical alternative to the self-destruction of such a damaged cell by
apoptosis Apoptosis (from Ancient Greek Ancient Greek includes the forms of the Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ) ...

apoptosis
.


Interphase

Interphase represent the phase between two successive M phases. Interphase is a series of changes that takes place in a newly formed cell and its nucleus before it becomes capable of division again. It is also called preparatory phase or intermitosis. Typically interphase lasts for at least 91% of the total time required for the cell cycle. Interphase proceeds in three stages, G1, S, and G2, followed by the cycle of mitosis and cytokinesis. The cell's nuclear DNA contents are duplicated during S phase.


G1 phase (First growth phase or Post mitotic gap phase)

The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis, is called G1 (G indicating ''gap''). It is also called the growth phase. During this phase, the biosynthetic activities of the cell, which are considerably slowed down during M phase, resume at a high rate. The duration of G1 is highly variable, even among different cells of the same species. In this phase, the cell increases its supply of proteins, increases the number of organelles (such as mitochondria, ribosomes), and grows in size. In G1 phase, a cell has three options. *To continue cell cycle and enter
S phase S phase (Synthesis Phase) is the phase of the cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may ...
*Stop cell cycle and enter G0 phase for undergoing
differentiation Differentiation may refer to: Business * Differentiation (economics), the process of making a product different from other similar products * Product differentiation, in marketing * Differentiated service, a service that varies with the identity o ...
. *Become arrested in G1 phase hence it may enter G0 phase or re-enter cell cycle. The deciding point is called
check point Check Point is an American-Israeli multinational provider of software and combined hardware and software products for IT security, including network security, endpoint security, cloud security, mobile security, data security and security manageme ...
(
Restriction point The restriction point (R), also known as the Start or G1/S checkpoint, is a cell cycle checkpoint Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potentia ...
). This
check point Check Point is an American-Israeli multinational provider of software and combined hardware and software products for IT security, including network security, endpoint security, cloud security, mobile security, data security and security manageme ...
is called the restriction point or START and is regulated by G1/S cyclins, which cause transition from G1 to S phase. Passage through the G1 check point commits the cell to division.


S phase (DNA replication)

The ensuing
S phase S phase (Synthesis Phase) is the phase of the cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may ...
starts when
DNA synthesis DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occurs w ...
commences; when it is complete, all of the
chromosome A chromosome is a long DNA molecule with part or all of the genome, genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones which, aided by Chaperone (protein), chaperone proteins, bind to and ...

chromosome
s have been replicated, i.e., each chromosome consists of two sister
chromatid In the diagram, (1) refers to a chromatid: 1-half of two identical threadlike strands of a replicated sister chromatid pair") are joined at the region called the centromere">ister_chromatids.html" ;"title="chromosome. During cell division, the ide ...
s. Thus, during this phase, the amount of DNA in the cell has doubled, though the
ploidy Ploidy () is the number of complete sets of chromosome A chromosome is a long DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, wh ...
and number of chromosomes are unchanged. Rates of RNA transcription and
protein synthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the product ...
are very low during this phase. An exception to this is
histone In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms ...
production, most of which occurs during the S phase.


G2 phase (growth)

G2 phase occurs after DNA replication and is a period of protein synthesis and rapid cell growth to prepare the cell for mitosis. During this phase microtubules begin to reorganize to form a spindle (preprophase). Before proceeding to
mitotic phase The cell cycle, or cell-division cycle, is the series of events that take place in a cell (biology), cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its Organe ...

mitotic phase
, cells must be checked at the G2 checkpoint for any DNA damage within the chromosomes. The G2 checkpoint is mainly regulated by the tumor protein
p53 Tumor protein P53, also known as p53, cellular p53 ( name), the Guardian of the Genome, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53), is any of a protein encoded by homologous s in v ...
. If the DNA is damaged, p53 will either repair the DNA or trigger the apoptosis of the cell. If p53 is dysfunctional or mutated, cells with damaged DNA may continue through the cell cycle, leading to the development of cancer.


Mitotic phase (chromosome separation)

The relatively brief ''M phase'' consists of nuclear division (
karyokinesis In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proces ...
). It is a relatively short period of the cell cycle. M phase is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These phases are sequentially known as: *
prophase Prophase () is the first stage of cell division in both mitosis and meiosis. Beginning after interphase, DNA has already been replicated when the Cell (biology), cell enters prophase. The main occurrences in prophase are the condensation of the ...

prophase
*
prometaphase Prometaphase is the phase of mitosis following prophase and preceding metaphase, in eukaryote, eukaryotic Somatic (biology), somatic Cell (biology), cells. In prometaphase, the nuclear membrane breaks apart into numerous "membrane vesicles", a ...

prometaphase
*
metaphase Metaphase () is a stage of mitosis In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical s ...

metaphase
*
anaphase Anaphase (from the Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country located in Southeast Europe. Its population is app ...

anaphase
*
telophase Fluorescence micrograph of a human cell in telophase showing chromosomes (DNA) in blue, microtubules in green and kinetochores in pink Telophase (from the Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el ...

telophase
Mitosis is the process by which a
eukaryotic Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...
cell separates the
chromosome A chromosome is a long DNA molecule with part or all of the genome, genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones which, aided by Chaperone (protein), chaperone proteins, bind to and ...

chromosome
s in its
cell nucleus In cell biology, the nucleus (pl. ''nuclei''; from Latin or , meaning ''kernel'' or ''seed'') is a biological membrane#Function, membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotes usually have a single n ...

cell nucleus
into two identical sets in two nuclei. During the process of mitosis the pairs of
chromosomes A chromosome is a long DNA molecule with part or all of the genome, genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones which, aided by Chaperone (protein), chaperone proteins, bind to and D ...
condense and attach to
microtubule Microtubules are polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecules, composed of many Repeat unit, rep ...

microtubule
s that pull the
sister chromatids A sister chromatid refers to the identical copies (chromatids) formed by the DNA replication of a chromosome, with both copies joined together by a common centromere. In other words, a sister chromatid may also be said to be 'one-half' of the dup ...
to opposite sides of the cell. Mitosis occurs exclusively in
eukaryotic Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...

eukaryotic
cells, but occurs in different ways in different species. For example, animal cells undergo an "open" mitosis, where the
nuclear envelope The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane A polarized membrane is a lipid bilayer, lipid membrane that has a positive electr ...

nuclear envelope
breaks down before the chromosomes separate, while
fungi A fungus (plural The plural (sometimes abbreviated An abbreviation (from Latin ''brevis'', meaning ''short'') is a shortened form of a word or phrase, by any method. It may consist of a group of letters, or words taken from the full ...

fungi
such as ''
Aspergillus nidulans ''Aspergillus nidulans'' (also called ''Emericella nidulans'' when referring to its sexual form, or teleomorph) is one of many species of filamentous fungi A fungus (plural The plural (sometimes list of glossing abbreviations, abbreviate ...

Aspergillus nidulans
'' and ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () is a species of yeast Yeasts are eukaryotic Eukaryotes () are organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms are ...

Saccharomyces cerevisiae
'' (
yeast Yeasts are eukaryotic Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular ...

yeast
) undergo a "closed" mitosis, where chromosomes divide within an intact
cell nucleus In cell biology, the nucleus (pl. ''nuclei''; from Latin or , meaning ''kernel'' or ''seed'') is a biological membrane#Function, membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotes usually have a single n ...

cell nucleus
.


Cytokinesis phase (separation of all cell components)

Mitosis is immediately followed by
cytokinesis Cytokinesis () is the part of the cell division biological process, process during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of Mitosis, nuclear di ...

cytokinesis
, which divides the nuclei,
cytoplasm In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes ...
,
organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, ...
s and
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane A biological membrane, biomembrane or cell membrane is a selectively permeable membra ...

cell membrane
into two cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the
division Division or divider may refer to: Mathematics *Division (mathematics), the inverse of multiplication *Division algorithm, a method for computing the result of mathematical division Military *Division (military), a formation typically consisting o ...

division
of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. This accounts for approximately 10% of the cell cycle. Because cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with "M phase". However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei in a process called
endoreplication Endoreduplication (also referred to as endoreplication or endocycling) is replication of the nuclear genome In the fields of molecular biology and genetics Genetics is a branch of biology concerned with the study of genes, genetic v ...
. This occurs most notably among the
fungi A fungus (plural The plural (sometimes abbreviated An abbreviation (from Latin ''brevis'', meaning ''short'') is a shortened form of a word or phrase, by any method. It may consist of a group of letters, or words taken from the full ...

fungi
and
slime mold Slime mold or slime mould is an informal name given to several kinds of unrelated organisms that can live freely as single cells, but can aggregate together to form multicellular reproductive structures. Slime molds were formerly classified ...

slime mold
s, but is found in various groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of
fruit fly
fruit fly
embryonic development. Errors in mitosis can result in cell death through
apoptosis Apoptosis (from Ancient Greek Ancient Greek includes the forms of the Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ) ...

apoptosis
or cause
mutation In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechan ...
s that may lead to
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumor A benign tumor is a mass of cells Cell most often refers to: * Cell (biolo ...

cancer
.


Regulation of eukaryotic cell cycle

Regulation of the cell cycle involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle.


Role of cyclins and CDKs

Two key classes of regulatory molecules,
cyclin Cyclin is a family of proteins that controls the progression of a cell through the cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell Cell most often refers to: * Cell (biology), the funct ...
s and
cyclin-dependent kinase Cyclin-dependent kinases (CDKs) are the families of s first discovered for their role in regulating the . They are also involved in regulating , mRNA processing, and the differentiation of nerve cells. They are present in all known , and their re ...
s (CDKs), determine a cell's progress through the cell cycle. Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001
Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly , native_name_lang = , image = Nobel Assembly at Karolinska Institutet.jpeg , size = , motto = , formation = 190113 March 1978(as a forma ...
for their discovery of these central molecules. Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general, more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especially ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () is a species of yeast Yeasts are eukaryotic Eukaryotes () are organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms are ...

Saccharomyces cerevisiae
''; genetic nomenclature in yeast dubs many of these genes ''cdc'' (for "cell division cycle") followed by an identifying number, e.g. ''
cdc25 Cdc25 is a dual-specificity phosphatase first isolated from the yeast ''Schizosaccharomyces pombe'' as a cell cycle defective mutant. As with other cell cycle proteins or genes such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell division c ...
'' or ''
cdc20 #REDIRECT CDC20#REDIRECT CDC20 The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the ''CDC20'' gene in humans. To the best of current knowledge its most important function is to activate the ana ...
''. Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated
heterodimer In biochemistry Biochemistry or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology ...
; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called
phosphorylation In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during ...

phosphorylation
that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals.


General mechanism of cyclin-CDK interaction

Upon receiving a pro-mitotic extracellular signal, G1
cyclin-CDK A cyclin-dependent kinase complex (CDKC, cyclin-CDK) is a formed by the association of an inactive catalytic subunit of a protein kinase, (CDK), with a regulatory subunit, .Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Bi ...
complexes become active to prepare the cell for S phase, promoting the expression of
transcription factor In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, m ...
s that in turn promote the expression of S cyclins and of enzymes required for
DNA replication In , DNA replication is the of producing two identical replicas of DNA from one original molecule. DNA replication occurs in all acting as the most essential part for . This is essential for cell division during growth and repair of damaged tis ...

DNA replication
. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for
ubiquitination Ubiquitin is a small (8.6 ) found in most tissues of organisms, i.e., it is found . It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the code for ubiquitin: , , and . ...
. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the
proteasome Proteasomes are protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chain Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Ancient Greek, ancient , ''Hellēn ...

proteasome
. However, results from a recent study of E2F transcriptional dynamics at the single-cell level argue that the role of G1 cyclin-CDK activities, in particular cyclin D-CDK4/6, is to tune the timing rather than the commitment of cell cycle entry. Active S cyclin-CDK complexes phosphorylate proteins that make up the
pre-replication complex A pre-replication complex (pre-RC) is a protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chain Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Ancient Greek ...
es assembled during G1 phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell's
genome In the fields of molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, M ...

genome
will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to
gene copy number Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variationGenomic structural variation is the ...
effects, possession of extra copies of certain genes is also deleterious to the daughter cells. Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of
mitosis In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proce ...

mitosis
by stimulating downstream proteins involved in chromosome condensation and
mitotic spindle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes ...
assembly. A critical complex activated during this process is a
ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Pe ...
known as the
anaphase-promoting complex Anaphase-promoting complex (also called the cyclosome or APC/C) is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin ...

anaphase-promoting complex
(APC), which promotes degradation of structural proteins associated with the chromosomal
kinetochore A kinetochore (, ) is a disc-shaped protein structure associated with duplicated chromatids in eukaryote, eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the cent ...

kinetochore
. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.


Specific action of cyclin-CDK complexes

Cyclin D Cyclin D is a member of the cyclin Cyclin is a family of proteins that controls the progression of a cell through the cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to ...
is the first cyclin produced in the cells that enter the cell cycle, in response to extracellular signals (e.g.
growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential gro ...
s). Cyclin D levels stay low in resting cells that are not proliferating. Additionally, CDK4/6 and
CDK2 Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzyme ...
are also inactive because CDK4/6 are bound by
INK4 INK4 is a family In , family (from la, familia) is a of people related either by (by recognized birth) or (by marriage or other relationship). The purpose of families is to maintain the well-being of its members and of society. Ideally, f ...
family members (e.g., p16), limiting kinase activity. Meanwhile, CDK2 complexes are inhibited by the CIP/KIP proteins such as p21 and p27, When it is time for a cell to enter the cell cycle, which is triggered by a mitogenic stimuli, levels of cyclin D increase. In response to this trigger, cyclin D binds to existing
CDK4 Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act a ...
/6, forming the active cyclin D-CDK4/6 complex. Cyclin D-CDK4/6 complexes in turn mono-phosphorylates the
retinoblastoma Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue (biology), tissue of the eye. It is the most common primary malignant intraocular cancer in children, and it is almo ...

retinoblastoma
susceptibility protein ( Rb) to pRb. The un-phosphorylated Rb tumour suppressor functions in inducing cell cycle exit and maintaining G0 arrest (senescence). In the last few decades, a model has been widely accepted whereby pRB proteins are inactivated by cyclin D-Cdk4/6-mediated phosphorylation. Rb has 14+ potential phosphorylation sites. Cyclin D-Cdk 4/6 progressively phosphorylates Rb to hyperphosphorylated state, which triggers dissociation of pRB–
E2F E2F is a group of genes that encodes a family of transcription factor In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biolo ...
complexes, thereby inducing G1/S cell cycle gene expression and progression into S phase. However, scientific observations from a recent study show that Rb is present in three types of isoforms: (1) un-phosphorylated Rb in G0 state; (2) mono-phosphorylated Rb, also referred to as "hypo-phosphorylated' or 'partially' phosphorylated Rb in early G1 state; and (3) inactive hyper-phosphorylated Rb in late G1 state. In early G1 cells, mono-phosphorylated Rb exits as 14 different isoforms, one of each has distinct
E2F E2F is a group of genes that encodes a family of transcription factor In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biolo ...
binding affinity. Rb has been found to associate with hundreds of different proteins and the idea that different mono-phosphorylated Rb isoforms have different protein partners was very appealing. A recent report confirmed that mono-phosphorylation controls Rb's association with other proteins and generates functional distinct forms of Rb. All different mono-phosphorylated Rb isoforms inhibit E2F transcriptional program and are able to arrest cells in G1-phase. Importantly, different mono-phosphorylated forms of RB have distinct transcriptional outputs that are extended beyond E2F regulation. In general, the binding of pRb to E2F inhibits the E2F target gene expression of certain G1/S and S transition genes including E-type cyclins. The partial phosphorylation of RB de-represses the Rb-mediated suppression of E2F target gene expression, begins the expression of cyclin E. The molecular mechanism that causes the cell switched to cyclin E activation is currently not known, but as cyclin E levels rise, the active cyclin E-CDK2 complex is formed, bringing Rb to be inactivated by hyper-phosphorylation. Hyperphosphorylated Rb is completely dissociated from E2F, enabling further expression of a wide range of E2F target genes are required for driving cells to proceed into S phase Recently, it has been identified that cyclin D-Cdk4/6 binds to a C-terminal alpha-helix region of Rb that is only distinguishable to cyclin D rather than other cyclins,
cyclin E Cyclin E is a member of the cyclin Cyclin is a family of proteins that controls the progression of a cell through the cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell Cell most often r ...
, A and B. This observation based on the structural analysis of Rb phosphorylation supports that Rb is phosphorylated in a different level through multiple Cyclin-Cdk complexes. This also makes feasible the current model of a simultaneous switch-like inactivation of all mono-phosphorylated Rb isoforms through one type of Rb hyper-phosphorylation mechanism. In addition, mutational analysis of the cyclin D- Cdk 4/6 specific Rb C-terminal helix shows that disruptions of cyclin D-Cdk 4/6 binding to Rb prevents Rb phosphorylation, arrests cells in G1, and bolsters Rb's functions in tumor suppressor. This cyclin-Cdk driven cell cycle transitional mechanism governs a cell committed to the cell cycle that allows cell proliferation. A cancerous cell growth often accompanies with deregulation of Cyclin D-Cdk 4/6 activity. The hyperphosphorylated Rb dissociates from the E2F/DP1/Rb complex (which was bound to the
E2F E2F is a group of genes that encodes a family of transcription factor In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biolo ...
responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like
cyclin E Cyclin E is a member of the cyclin Cyclin is a family of proteins that controls the progression of a cell through the cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell Cell most often r ...
,
cyclin A Cyclin A is a member of the cyclin Cyclin is a family of proteins that controls the progression of a cell through the cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to di ...
,
DNA polymerase A DNA polymerase is a member of a family of enzyme Enzymes () are s that act as s (biocatalysts). Catalysts accelerate . The molecules upon which enzymes may act are called , and the enzyme converts the substrates into different molecules ...

DNA polymerase
,
thymidine kinase Thymidine kinase is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the ...

thymidine kinase
, etc. Cyclin E thus produced binds to
CDK2 Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzyme ...
, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S, which initiates the G2/M transition).
Cyclin B Cyclin B is a member of the cyclin Cyclin is a family of proteins that controls the progression of a cell through the cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell Cell most often ...
-cdk1 complex activation causes breakdown of
nuclear envelope The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane A polarized membrane is a lipid bilayer, lipid membrane that has a positive electr ...

nuclear envelope
and initiation of
prophase Prophase () is the first stage of cell division in both mitosis and meiosis. Beginning after interphase, DNA has already been replicated when the Cell (biology), cell enters prophase. The main occurrences in prophase are the condensation of the ...

prophase
, and subsequently, its deactivation causes the cell to exit mitosis. A quantitative study of E2F transcriptional dynamics at the single-cell level by using engineered fluorescent reporter cells provided a quantitative framework for understanding the control logic of cell cycle entry, challenging the canonical textbook model. Genes that regulate the amplitude of E2F accumulation, such as Myc, determine the commitment in cell cycle and S phase entry. G1 cyclin-CDK activities are not the driver of cell cycle entry. Instead, they primarily tune the timing of E2F increase, thereby modulating the pace of cell cycle progression.


Inhibitors


Endogenous

Two families of genes, the ''cip/kip'' (''CDK interacting protein/Kinase inhibitory protein'') family and the INK4a/ARF (''In''hibitor of ''K''inase 4/''A''lternative ''R''eading ''F''rame) family, prevent the progression of the cell cycle. Because these genes are instrumental in prevention of
tumor A neoplasm () is a type of abnormal and excessive growth of tissue Tissue may refer to: Biology * Tissue (biology), an ensemble of similar cells that together carry out a specific function * ''Triphosa haesitata'', a species of geometer moth ...

tumor
formation, they are known as
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular bio ...
s. The ''cip/kip'' family includes the genes
p21 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor A cyclin-dependent kinase inhibitor protein is a protein which inhibits the enzyme cyclin ...

p21
, p27 and p57. They halt the cell cycle in G1 phase by binding to and inactivating cyclin-CDK complexes. p21 is activated by
p53 Tumor protein P53, also known as p53, cellular tumor antigen Tumor antigen is an antigenic substance produced in tumor Cell (biology), cells, i.e., it triggers an immune response in the Host (biology), host. Tumor antigens are useful tumor mar ...

p53
(which, in turn, is triggered by DNA damage e.g. due to radiation). p27 is activated by Transforming Growth Factor β ( TGF β), a growth inhibitor. The INK4a/ARF family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14ARF which prevents p53 degradation.


Synthetic

Synthetic inhibitors of
Cdc25 Cdc25 is a dual-specificity phosphatase In biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science () is a systematic enterprise that Scientific method, builds and organizes know ...
could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents. Many human cancers possess the hyper-activated Cdk 4/6 activities. Given the observations of cyclin D-Cdk 4/6 functions, inhibition of Cdk 4/6 should result in preventing a malignant tumor from proliferating. Consequently, scientists have tried to invent the synthetic Cdk4/6 inhibitor as Cdk4/6 has been characterized to be a therapeutic target for anti-tumor effectiveness. Three Cdk4/6 inhibitors -
palbociclib Palbociclib, sold under the brand name Ibrance among others, is a medication drug development, developed by Pfizer for the treatment of HR-positive and HER2-negative breast cancer. It is a selective enzyme inhibitor, inhibitor of the cyclin-depend ...

palbociclib
,
ribociclib Ribociclib, sold under the brand name Kisqali, is an inhibitor of cyclin D1/CDK4 and CDK6, and is used for the treatment of certain kinds of breast cancer. on Kisqali. Accessed 2017-09-08. It is also being studied as a treatment for other drug-resi ...
, and - currently received FDA approval for clinical use to treat advanced-stage or
metastatic Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
, hormone-receptor-positive (HR-positive, HR+), HER2-negative (HER2-) breast cancer. For example, palbociclib is an orally active CDK4/6 inhibitor which has demonstrated improved outcomes for ER-positive/HER2-negative advanced breast cancer. The main side effect is
neutropenia Neutropenia is an abnormally low concentration of neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cell White blood cells (WBCs), also c ...

neutropenia
which can be managed by dose reduction. Cdk4/6 targeted therapy will only treat cancer types where Rb is expressed. Cancer cells with loss of Rb have primary resistance to Cdk4/6 inhibitors.


Transcriptional regulatory network

Current evidence suggests that a semi-autonomous transcriptional network acts in concert with the CDK-cyclin machinery to regulate the cell cycle. Several gene expression studies in ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () is a species of yeast Yeasts are eukaryotic Eukaryotes () are organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms are ...

Saccharomyces cerevisiae
'' have identified 800–1200 genes that change expression over the course of the cell cycle. They are transcribed at high levels at specific points in the cell cycle, and remain at lower levels throughout the rest of the cycle. While the set of identified genes differs between studies due to the computational methods and criteria used to identify them, each study indicates that a large portion of yeast genes are temporally regulated. Many periodically expressed genes are driven by
transcription factor In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, m ...
s that are also periodically expressed. One screen of single-gene knockouts identified 48 transcription factors (about 20% of all non-essential transcription factors) that show cell cycle progression defects. Genome-wide studies using high throughput technologies have identified the transcription factors that bind to the promoters of yeast genes, and correlating these findings with temporal expression patterns have allowed the identification of transcription factors that drive phase-specific gene expression. The expression profiles of these transcription factors are driven by the transcription factors that peak in the prior phase, and computational models have shown that a CDK-autonomous network of these transcription factors is sufficient to produce steady-state oscillations in gene expression). Experimental evidence also suggests that gene expression can oscillate with the period seen in dividing wild-type cells independently of the CDK machinery. Orlando ''et al.'' used
microarray A microarray is a multiplex Multiplex may refer to: * Multiplex (automobile), a former American car make * Multiplex (comics), a DC comic book supervillain * Multiplex communication or multiplexing, combining many signals into a single transmiss ...

microarray
s to measure the expression of a set of 1,271 genes that they identified as periodic in both wild type cells and cells lacking all S-phase and mitotic cyclins (''clb1,2,3,4,5,6''). Of the 1,271 genes assayed, 882 continued to be expressed in the cyclin-deficient cells at the same time as in the wild type cells, despite the fact that the cyclin-deficient cells arrest at the border between G1 and
S phase S phase (Synthesis Phase) is the phase of the cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may ...
. However, 833 of the genes assayed changed behavior between the wild type and mutant cells, indicating that these genes are likely directly or indirectly regulated by the CDK-cyclin machinery. Some genes that continued to be expressed on time in the mutant cells were also expressed at different levels in the mutant and wild type cells. These findings suggest that while the transcriptional network may oscillate independently of the CDK-cyclin oscillator, they are coupled in a manner that requires both to ensure the proper timing of cell cycle events. Other work indicates that
phosphorylation In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during ...

phosphorylation
, a post-translational modification, of cell cycle transcription factors by
Cdk1 Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckt ...
may alter the localization or activity of the transcription factors in order to tightly control timing of target genes. While oscillatory transcription plays a key role in the progression of the yeast cell cycle, the CDK-cyclin machinery operates independently in the early embryonic cell cycle. Before the
midblastula transition In developmental biology, midblastula or midblastula transition (MBT) occurs during the blastula stage of embryonic development. During this stage, the embryo is referred to as a blastula. The series of changes to the blastula that characterize t ...
, zygotic transcription does not occur and all needed proteins, such as the B-type cyclins, are translated from maternally loaded
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA i ...

mRNA
.


DNA replication and DNA replication origin activity

Analyses of synchronized cultures of ''Saccharomyces cerevisiae'' under conditions that prevent DNA replication initiation without delaying cell cycle progression showed that origin licensing decreases the expression of genes with origins near their 3' ends, revealing that downstream origins can regulate the expression of upstream genes. This confirms previous predictions from mathematical modeling of a global causal coordination between DNA replication origin activity and mRNA expression, and shows that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation.


Checkpoints

Cell cycle checkpoint Cell cycle checkpoints are control mechanisms in the eukaryotic Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Bioch ...
s are used by the cell to monitor and regulate the progress of the cell cycle. Checkpoints prevent cell cycle progression at specific points, allowing verification of necessary phase processes and repair of
DNA damage DNA repair is a collection of processes by which a identifies and corrects damage to the molecules that encode its . In human cells, both normal activities and environmental factors such as can cause DNA damage, resulting in tens of thousan ...
. The cell cannot proceed to the next phase until checkpoint requirements have been met. Checkpoints typically consist of a network of regulatory proteins that monitor and dictate the progression of the cell through the different stages of the cell cycle. It is estimated that in normal human cells about 1% of single-strand DNA damages are converted to about 50 endogenous DNA double-strand breaks per cell per cell cycle.Vilenchik MM, Knudson AG. Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12871-6. doi: 10.1073/pnas.2135498100. Epub 2003 Oct 17. PMID: 14566050; PMCID: PMC240711. Although such double-strand breaks are usually with high fidelity, errors in their repair are considered to contribute significantly to the rate of cancer in humans. There are several checkpoints to ensure that damaged or incomplete DNA is not passed on to daughter cells. Three main checkpoints exist: the G1/S checkpoint, the G2/M checkpoint and the metaphase (mitotic) checkpoint. Another checkpoint is the Go checkpoint, in which the cells are checked for maturity. If the cells fail to pass this checkpoint by not being ready yet, they will be discarded from dividing. G1/S transition is a rate-limiting step in the cell cycle and is also known as
restriction point The restriction point (R), also known as the Start or G1/S checkpoint, is a cell cycle checkpoint Cell cycle checkpoints are control mechanisms in the eukaryotic Eukaryotes () are organism In biology Biology is the natura ...
. This is where the cell checks whether it has enough raw materials to fully replicate its DNA (nucleotide bases, DNA synthase, chromatin, etc.). An unhealthy or malnourished cell will get stuck at this checkpoint. The G2/M checkpoint is where the cell ensures that it has enough cytoplasm and phospholipids for two daughter cells. But sometimes more importantly, it checks to see if it is the right time to replicate. There are some situations where many cells need to all replicate simultaneously (for example, a growing embryo should have a symmetric cell distribution until it reaches the mid-blastula transition). This is done by controlling the G2/M checkpoint. The metaphase checkpoint is a fairly minor checkpoint, in that once a cell is in metaphase, it has committed to undergoing mitosis. However that's not to say it isn't important. In this checkpoint, the cell checks to ensure that the spindle has formed and that all of the chromosomes are aligned at the spindle equator before anaphase begins. While these are the three "main" checkpoints, not all cells have to pass through each of these checkpoints in this order to replicate. Many types of cancer are caused by mutations that allow the cells to speed through the various checkpoints or even skip them altogether. Going from S to M to S phase almost consecutively. Because these cells have lost their checkpoints, any DNA mutations that may have occurred are disregarded and passed on to the daughter cells. This is one reason why cancer cells have a tendency to exponentially accrue mutations. Aside from cancer cells, many fully differentiated cell types no longer replicate so they leave the cell cycle and stay in G0 until their death. Thus removing the need for cellular checkpoints. An alternative model of the cell cycle response to DNA damage has also been proposed, known as the postreplication checkpoint. Checkpoint regulation plays an important role in an organism's development. In sexual reproduction, when egg fertilization occurs, when the sperm binds to the egg, it releases signalling factors that notify the egg that it has been fertilized. Among other things, this induces the now fertilized oocyte to return from its previously dormant, G0, state back into the cell cycle and on to mitotic replication and division.
p53 Tumor protein P53, also known as p53, cellular tumor antigen Tumor antigen is an antigenic substance produced in tumor Cell (biology), cells, i.e., it triggers an immune response in the Host (biology), host. Tumor antigens are useful tumor mar ...

p53
plays an important role in triggering the control mechanisms at both G1/S and G2/M checkpoints. In addition to p53, checkpoint regulators are being heavily researched for their roles in cancer growth and proliferation.


Fluorescence imaging of the cell cycle

Pioneering work by Atsushi Miyawaki and coworkers developed the fluorescent ubiquitination-based cell cycle indicator
FUCCI
, which enables
fluorescence Fluorescence is the emission of light Light or visible light is electromagnetic radiation within the portion of the electromagnetic spectrum that is visual perception, perceived by the human eye. Visible light is usually defined as ha ...

fluorescence
imaging of the cell cycle. Originally, a
green fluorescent protein The green fluorescent protein (GFP) is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John ...
, mAG, was fused to hGem(1/110) and an orange
fluorescent proteinFluorescent proteins include: * Green fluorescent protein (GFP) * Yellow fluorescent protein (YFP) * Red fluorescent protein (RFP) {{Short pages monitor