Shelterin (also called telosome) is a protein complex known to protect

telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...

s in many

eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

s from DNA repair mechanisms, as well as to regulate

telomerase Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most euka ...

activity. In mammals and other vertebrates, telomeric DNA consists of repeating double-stranded 5'-TTAGGG-3' (G-strand) sequences (2-15 kilobases in humans) along with the 3'-AATCCC-5' (C-strand) complement, ending with a 50-400

nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...

3' (G-strand) overhang. Much of the final double-stranded portion of the telomere forms a T-loop (Telomere-loop) that is invaded by the 3' (G-strand) overhang to form a small

D-loop In molecular biology, a displacement loop or D-loop is a DNA structure where the two strands of a double-stranded DNA molecule are separated for a stretch and held apart by a third strand of DNA. An R-loop is similar to a D-loop, but in this cas ...

(Displacement-loop). The absence of shelterin causes telomere uncapping and thereby activates damage-signaling pathways that may lead to

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 direct ...

(NHEJ),

homology directed repair Homology-directed repair (HDR) is a mechanism in cells to repair double-strand DNA lesions. The most common form of HDR is homologous recombination. The HDR mechanism can only be used by the cell when there is a homologous piece of DNA presen ...

(HDR), end-to-end fusions, genomic instability,

senescence Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...

, or

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

Subunits

Shelterin has six subunits: TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. They can operate in smaller subsets to regulate the length of or to protect telomeres. *

TRF1 The TRF1 is a 155mm French towed howitzer produced by Nexter (ex Giat Industries) and used by the French Army. The TRF1 was showcased in 1979 at the Eurosatory arms trade show, as a replacement for Armée de Terre's BF-50. Giat produced it fro ...

(Telomere Repeat binding Factor 1): TRF1 is a

homodimeric In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...

protein that binds to the double-stranded TTAGGG region of the telomere. TRF1 along with TRF2 normally prevents telomerase from adding more telomere units to telomeres. But when telomere lengthening is required, TRF1 recruits

helicase Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separatin ...

s and interacts with tankyrases to facilitate the process. TRF1 is highly expressed in

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

s, and is essential for generation of

induced pluripotent stem cell Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka's lab in Kyoto, Japan, who showed in ...

s. TRF1 is

upregulated In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proce ...

in the brain cancer

glioblastoma multiforme Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...

(GBM) in humans and mice, because of stem-cell quality of the cancer. Genetic ablation and chemical inhibition of TRF1 in mouse models of the brain cancer glioblastoma, and chemical inhibition of cultured human GBM cells inhibited tumor growth. TRF1 levels decrease with aging in humans and in mice. Increasing TRF1 in mice by

gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...

( AAV9 delivery) improved memory and other measures of health span. Conversely, inhibition of the PI3K/AKT pathway decreases TRF1, resulting in telomere-induced DNA damage. TRF1 may recruit

PINX1 ''PIN2/TERF1''-interacting telomerase inhibitor 1, also known as ''PINX1'', is a human gene. ''PINX1'' is also known as ''PIN2'' interacting protein 1. ''PINX1'' is a telomerase inhibitor and a possible tumor suppressor. Interactions PINX1 has be ...

to inhibit telomere elongation by telomerase. * TRF2 (Telomere Repeat binding Factor 2) TRF2 is structurally related to TRF1, and helps to form T-loops. TRF2 is a homodimeric protein that binds to the double-stranded TTAGGG region of the telomere and prevents the recognition of double-strand DNA breaks. Overexpression of TRF2 leads to telomere shortening. Loss of TRF2 which leads to loss of the T-loop can activate

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

or ATM-mediated apoptosis. * Both TRF1 and TRF2 recruit the other four subunits to the telomere. Both TRF1 and TRF2 participate in telomere replication as well as in the prevention of replication fork stalling. Exercise has been shown to

upregulate In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pro ...

both TRF1 and TRF2 in

leukocytes White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

as well as

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

, thereby protecting against

. * RAP1 (Repressor / Activator Protein 1): RAP1 is a stabilizing protein associated with TRF2. RAP1 inhibits

DNA repair 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 dam ...

. *

POT1 Protection of telomeres protein 1 is a protein that in humans is encoded by the ''POT1'' gene. Function This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein func ...

(Protection of Telomere 1): POT1 contains OB-folds (oligonucleotide/oligosaccharide binding) that bind POT1 to single-stranded DNA, which increase its affinity for single-stranded TTAGGG region of telomeric DNA. POT1 helps form the telomere-stabilizing D-loop. POT1 prevents the degradation of this single stranded DNA by

nuclease A nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds between nucleotides of nucleic acids. Nucleases variously effect single and double stranded breaks in their ta ...

s and shelters the 3' G-overhang. POT1 suppresses

ATR ATR may refer to: Medicine * Acute transfusion reaction * Ataxia telangiectasia and Rad3 related, a protein involved in DNA damage repair Science and mathematics * Advanced Test Reactor, nuclear research reactor at the Idaho National Laboratory, ...

-mediated DNA repair. Humans only have a single POT1, whereas mice have POT1a and POT1b. POT1a inhibits DNA damage repair at the telomere, whereas POT1b regulates the length of telomeric single-stranded DNA. * TPP1 (

ACD (gene) Adrenocortical dysplasia protein homolog is a protein that in humans is encoded by the ''ACD'' gene. Function This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin ...

): TPP1 is a protein associated with POT1. The loss of TPP1 leads to impaired POT1 function. When telomeres are to be lengthened, TPP1 is a central factor in recruiting telomerase to telomeres. TPP1 promotes telomerase processivity in the presence of POT1. But interaction with the

CST Complex The CST complex is a cellular multiprotein complex involved in telomere maintenance. In budding yeast (''Saccharomyces cerevisiae''), it is composed of the proteins Cdc13, Stn1, and Ten1; in mammals, it consists of the proteins CTC1, STN1, and TEN ...

limits excessive telomere elongation by telomerase. The gene which encodes for TPP1 ( ACD) is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I. * TIN2 (TRF1- and TRF2-Interacting Nuclear Protein 2) TIN2 is a stabilizing protein that binds to the TRF1, TRF2, and the TPP1-POT1 complex. thereby bridging units attached to double-stranded DNA and units attached to single-stranded DNA.

Repression of DNA repair mechanisms

There are two main DNA-damage-signaling pathways that shelterin represses: the ATR kinase pathway, blocked by POT1, and the ATM kinase pathway, blocked by TRF2. In the ATR kinase pathway, ATR and ATRIP sense the presence of single-stranded DNA and induce a phosphorylation cascade that leads to cell cycle arrest. To prevent this signal, POT1 "shelters" the single-stranded region of telomeric DNA. The ATM kinase pathway, which starts from ATM and other proteins sensing double strand breaks, similarly ends with cell cycle arrest. TRF2 may also hide the ends of telomeres, just as POT1 hides the single-stranded regions. Another theory proposes the blocking of the signal downstream. This will lead to a dynamic instability of the cells over time. The structure of the t-loop may prevent NHEJ. For NHEJ to occur, the Ku heterodimer must be able to bind to the ends of the chromosome. Another theory offers the mechanism proposed earlier: TRF2 hides the ends of telomeres.

Species differences

At least four factors contribute to telomere maintenance in most eukaryotes:

, shelterin,

TERRA Terra may often refer to: * Terra (mythology), primeval Roman goddess * An alternate name for planet Earth, as well as the Latin name for the planet Terra may also refer to: Geography Astronomy * Terra (satellite), a multi-national NASA scienti ...

and the

. Fission yeast (

Schizosaccharomyces pombe ''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically meas ...

) has a shelterin complex for protection and maintenance of telomeres, but in

budding yeast ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...

(

Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...

) this function is performed by the CST Complex. For fission yeast, Rap1 and Pot1 are conserved, but Tpz1 is an

ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

of TPP1 and Taz1 is an ortholog of TRF1 and TRF2. Plants contain a variety of telomere-protecting proteins which can resemble either shelterin or the CST Complex. The fruit fly ''

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...

'' lacks both shelterin and

, but instead uses

retrotransposon Retrotransposons (also called Class I transposable elements or transposons via RNA intermediates) are a type of genetic component that copy and paste themselves into different genomic locations (transposon) by converting RNA back into DNA through ...

s to maintain telomeres.

Non-telomeric functions of shelterin proteins

TIN2 can localize to

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

where it promotes

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...

. TIN2 loss in human cancer cells has resulted in reduced glycolysis and increased

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...

. RAP1 regulates transcription and affects

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

signaling.

References

{{reflist Protein complexes Telomere-binding proteins Telomere-related proteins

Subunits

Repression of DNA repair mechanisms

Species differences

Non-telomeric functions of shelterin proteins

See also

References