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 (see #Sequences, Sequences). Telomeres are a widespread genetic feature most commonly found in eukaryotes. In ...

s in many

eukaryote The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

s from

DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...

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 compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

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 (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. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...

(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 Function (biology), functional characteristics in living organisms. Whole organism senescence involves an increase in mortality rate, death rates or a decrease in fecundity with ...

, or

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

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. In the cells of mice and humans, TRF1, TRF2, TIN2, and RAP1 are about ten times more abundant than TPP1 and POT1. * TRF1 (Telomere Repeat binding Factor 1): TRF1 is a homodimeric protein that binds to the double-stranded TTAGGG region of the telomere. TRF1 along with TRF2 normally prevents

from adding more telomere units to telomeres. But when telomere lengthening is required, TRF1 recruits

helicase Helicases are a class of enzymes that are 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 double helix, separating the two hybridized ...

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 change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...

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 and Kazutoshi Takahashi in Kyoto, Jap ...

s. TRF1 is upregulated in the brain cancer glioblastoma multiforme (GBM) in humans and mice, because of the 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 Health technology, medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells. The first attempt at modifying human DNA ...

( 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 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 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 both TRF1 and TRF2 in

leukocytes White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

as well as

endothelial cells The endothelium (: endothelia) 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 res ...

, thereby protecting against

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

. *

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 fu ...

(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 In biochemistry, a nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds that link nucleotides together to form nucleic acids. Nucleases variously affect single and ...

s and shelters the 3' G-overhang. POT1 suppresses ATR-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: TPP1 is a protein associated with POT1, which is encoded by the ACD (gene). 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 is the only shelterin protein in direct contact with telomerase. TPP1 promotes telomerase processivity in the presence of POT1. But interaction with the CST Complex 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 TRF1, TRF2, and the TPP1-POT1 complex. thereby bridging units attached to double-stranded DNA and units attached to single-stranded DNA. TIN2 seems to affect telomerase activity, without being in direct contact with that enzyme.

Repression of
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
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. TIN2 and TRF2 independently block accumulation of the DNA repair enzyme PARP1 at telomeres. 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 and the CST Complex. 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 ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...

) this function is performed by the CST Complex. For fission yeast, Rap1 and Pot1 are conserved, but Tpz1 is an ortholog 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 (an insect of the Order (biology), 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", "pomace fly" ...

'' lacks both shelterin and

, but instead uses

retrotransposon Retrotransposons (also called Class I transposable elements) are mobile elements which move in the host genome by converting their transcribed RNA into DNA through reverse transcription. Thus, they differ from Class II transposable elements, or ...

s to maintain telomeres.

Non-telomeric functions of shelterin proteins

TIN2 can localize to

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

where it promotes

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...

. 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 Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...

. RAP1 regulates transcription and affects

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...

signaling.

References

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

Subunits

Repression of DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ... mechanisms

Species differences

Non-telomeric functions of shelterin proteins

See also

References

Repression of
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
mechanisms