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Microhomology-mediated End Joining
Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand breaks in DNA. As reviewed by McVey and Lee, the foremost distinguishing property of MMEJ is the use of microhomologous sequences during the alignment of broken ends before joining, thereby resulting in deletions flanking the original break. MMEJ is frequently associated with chromosome abnormalities such as deletions, translocations, inversions and other complex rearrangements. There are multiple pathways for repairing double strand breaks, mainly non-homologous end joining (NHEJ), homologous recombination (HR), and MMEJ. NHEJ directly joins both ends of the double strand break and is relatively accurate, although small (usually less than a few nucleotides) insertions or deletions sometimes occur. HR is highly accurate and uses the sister chromatid as a template for accurate repair of the DSB. MMEJ is distinguished from these ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Double-strand Break
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages (interstrand crosslinks or ICLs). This can eventually lead to malignan ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Non-homologous End Joining
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair(HDR), which requires a homologous sequence to guide repair. NHEJ is active in both non-dividing and proliferating cells, while HDR is not readily accessible in non-dividing cells. The term "non-homologous end joining" was coined in 1996 by Moore and Haber. NHEJ is typically guided by short homologous DNA sequences called microhomologies. These microhomologies are often present in single-stranded overhangs on the ends of double-strand breaks. When the overhangs are perfectly compatible, NHEJ usually repairs the break accurately. Imprecise repair leading to loss of nucleotides can also occur, but is much more common when the overhangs are not compatible. Inappropriate NHEJ can lead to translocations and telomere fusion, hallmarks ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Homologous Recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be also RNA in viruses). Homologous recombination is widely used by cells to accurately DNA repair harmful breaks that occur on both strands of DNA, known as double-strand breaks (DSB), in a process called homologous recombinational repair (HRR). Homologous recombination also produces new combinations of DNA sequences during meiosis, the process by which eukaryotes make gamete cells, like sperm and egg cells in animals. These new combinations of DNA represent genetic variation in offspring, which in turn enables populations to adapt during the course of evolution. Homologous recombination is also used in horizontal gene transfer to exchange genetic material between different strains and species of bacteria and viruses. Horizontal ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Ku (protein)
Ku is a dimeric protein complex that binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. Ku is evolutionarily conserved from bacteria to humans. The ancestral bacterial Ku is a homodimer (two copies of the same protein bound to each other). Eukaryotic Ku is a heterodimer of two polypeptides, Ku70 (XRCC6) and Ku80 (XRCC5), so named because the molecular weight of the human Ku proteins is around 70 kDa and 80 kDa. The two Ku subunits form a basket-shaped structure that threads onto the DNA end. Once bound, Ku can slide down the DNA strand, allowing more Ku molecules to thread onto the end. In higher eukaryotes, Ku forms a complex with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the full DNA-dependent protein kinase, DNA-PK. Ku is thought to function as a molecular scaffold to which other proteins involved in NHEJ can bind, orienting the double-strand break for ligation. The Ku70 and ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
DNA-PKcs
DNA-dependent protein kinase, catalytic subunit, also known as DNA-PKcs, is an enzyme that in humans is encoded by the gene designated as ''PRKDC'' or ''XRCC7''. DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. The DNA-Pkcs protein is a serine/threonine protein kinase comprising a single polypeptide chain of 4,128 amino acids. Function DNA-PKcs is the catalytic subunit of a nuclear DNA-dependent serine/threonine protein kinase called DNA-PK. The second component is the autoimmune antigen Ku. On its own, DNA-PKcs is inactive and relies on Ku to direct it to DNA ends and trigger its kinase activity. DNA-PKcs is required for the non-homologous end joining (NHEJ) pathway of DNA repair, which rejoins double-strand breaks. It is also required for V(D)J recombination, a process that utilizes NHEJ to promote immune system diversity. DNA-PKcs knockout mice have severe combined immunodeficiency due to their V(D)J recombination defect. Many proteins ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
S-phase
S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved. Regulation Entry into S-phase is controlled by the G1 restriction point (R), which commits cells to the remainder of the cell-cycle if there is adequate nutrients and growth signaling. This transition is essentially irreversible; after passing the restriction point, the cell will progress through S-phase even if environmental conditions become unfavorable. Accordingly, entry into S-phase is controlled by molecular pathways that facilitate a rapid, unidirectional shift in cell state. In yeast, for instance, cell growth induces accumulation of Cln3 cyclin, which complexes with the cyclin dependent kinase CDK2. The Cln3-CDK2 complex promotes transcription of S-phase genes by inactivating t ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Mutagen
In genetics, a mutagen is a physical or chemical agent that permanently changes nucleic acid, genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in animals, such mutagens can therefore be carcinogens, although not all necessarily are. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes. The process of DNA becoming modified is called mutagenesis. Not all mutations are caused by mutagens: so-called "spontaneous mutations" occur due to spontaneous hydrolysis, DNA error, errors in DNA replication, repair and Genetic recombination, recombination. Discovery The first mutagens to be identified were carcinogens, substances that were shown to be linked to cancer. Tumors were described more than 2,000 years before the discovery of chromosomes and DNA; in 500 B.C., the Greece, Greek physician Hippocrates named tu ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
FEN1
Flap endonuclease 1 is an enzyme that in humans is encoded by the ''FEN1'' gene. Function The protein encoded by this gene removes 5' overhanging "flaps" (or short sections of single stranded DNA that "hang off" because their nucleotide bases are prevented from binding to their complementary base pair—despite any base pairing downstream) in DNA repair and processes the 5' ends of Okazaki fragments in lagging strand DNA synthesis. Direct physical interaction between this protein and AP endonuclease 1 during long-patch base excision repair provides coordinated loading of the proteins onto the substrate, thus passing the substrate from one enzyme to another. The protein is a member of the XPG/RAD2 endonuclease family and is one of ten proteins essential for cell-free DNA replication. DNA secondary structure can inhibit flap processing at certain trinucleotide repeats in a length-dependent manner by concealing the 5' end of the flap that is necessary for both binding and cleavage ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
LIG3
DNA ligase 3 is an enzyme that, in humans, is encoded by the LIG3 gene. The human LIG3 gene encodes ATP-dependent DNA ligases that seal interruptions in the phosphodiester backbone of duplex DNA. There are three families of ATP-dependent DNA ligases in eukaryotes. These enzymes utilize the same three step reaction mechanism; (i) formation of a covalent enzyme-adenylate intermediate; (ii) transfer of the adenylate group to the 5’ phosphate terminus of a DNA nick; (iii) phosphodiester bond formation. Unlike LIG1 and LIG4 family members that are found in almost all eukaryotes, LIG3 family members are less widely distributed. The LIG3 gene encodes several distinct DNA ligase species by alternative translation initiation and alternative splicing mechanisms that are described below. Structure, DNA binding and catalytic activities Eukaryotic ATP-dependent DNA ligases have related catalytic region that contains three domains, a DNA binding domain, an adenylation domain and an olig ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
MRE11A
Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the ''MRE11'' gene. The gene has been designated ''MRE11A'' to distinguish it from the pseudogene ''MRE11B'' that is nowadays named ''MRE11P1''. Function This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms. Orthologs Mre11, a ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Nibrin
Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the ''NBN'' gene. Function Nibrin is a protein associated with the repair of double strand breaks (DSBs) which pose serious damage to a genome. It is a 754 amino acid protein identified as a member of the NBS1/hMre11/RAD50(N/M/R, more commonly referred to as MRN) double strand DNA break repair complex. This complex recognizes DNA damage and rapidly relocates to DSB sites and forms nuclear foci. It also has a role in regulation of N/M/R (MRN) protein complex activity which includes end-processing of both physiological and mutagenic DNA double strand breaks (DSBs). Cellular response to DSBs Cellular response is performed by damage sensors, effectors of lesion repair and signal transduction. The central role is carried out by ataxia telangiectasia mutated (ATM) by activating the DSB signaling cascade, phosphorylating downstream substrates such as histone H2AX and NBS1. NBS1 relocates to DSB sites ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
PARP1
Poly DP-ribosepolymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly DP-ribosesynthase 1 is an enzyme that in humans is encoded by the ''PARP1'' gene. It is the most abundant of the PARP family of enzymes, accounting for 90% of the NAD+ used by the family. PARP1 is mostly present in cell nucleus, but cytosolic fraction of this protein was also reported. Function PARP1 works: * By using NAD+ to synthesize poly ADP ribose (PAR) and transferring PAR moieties to proteins (ADP-ribosylation). * In conjunction with BRCA, which acts on double strands; members of the PARP family act on single strands; or, when BRCA fails, PARP takes over those jobs as well (in a DNA repair context). PARP1 is involved in: * Differentiation, proliferation, and tumor transformation * Normal or abnormal recovery from DNA damage * May be the site of mutation in Fanconi anemia * Induction of inflammation. * The pathophysiology of type I diabetes. PARP1 is activated by: * Helicobacte ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
