Shelterin
Shelterin (also called telosome) is a protein complex known to protect telomeres in many eukaryotes from DNA repair mechanisms, as well as to regulate telomerase 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 3' (G-strand) overhang.[1][2] 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).[1][3]
The absence of shelterin causes telomere uncapping and thereby activates damage-signaling pathways[4] that may lead to non-homologous end joining (NHEJ), homology directed repair (HDR),[5] end-to-end fusions,[6] genomic instability,[6] senescence, or apoptosis.[7]
Subunits
Shelterin has six subunits: TRF1, TRF2, POT1, RAP1, TIN2, and TPP1.[8] 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.[9]
- tankyrases[12] to facilitate the process. TRF1 is highly expressed in stem cells, and is essential for generation of induced pluripotent stem cells.[13] TRF1 is upregulated in the brain cancer glioblastoma multiforme (GBM) in humans and mice, because of the stem-cell quality of the cancer.[14] 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.[14] TRF1 levels decrease with aging in humans and in mice.[15] Increasing TRF1 in mice by gene therapy (AAV9 delivery) improved memory and other measures of health span.[15] Conversely, inhibition of the PI3K/AKT pathway decreases TRF1, resulting in telomere-induced DNA damage.[16] TRF1 may recruit PINX1 to inhibit telomere elongation by telomerase.[7]
- TRF2 (Telomere Repeat binding Factor 2) TRF2 is structurally related to TRF1, and helps to form T-loops.[6] TRF2 is a homodimeric protein[1] that binds to the double-stranded TTAGGG region of the telomere and prevents the recognition of double-strand DNA breaks.[17] Overexpression of TRF2 leads to telomere shortening.[6] Loss of TRF2 which leads to loss of the T-loop can activate p53 or ATM-mediated apoptosis.[18]
- Both TRF1 and TRF2 recruit the other four subunits to the telomere.replication fork stalling.[19] Exercise has been shown to upregulate both TRF1 and TRF2 in leukocytes as well as endothelial cells, thereby protecting against apoptosis.[20]
- RAP1 (Repressor / Activator Protein 1): RAP1 is a stabilizing protein associated with TRF2.[21] RAP1 inhibits DNA repair.[22]
- POT1 (Protection of Telomere 1): POT1 contains OB-folds (Oligonucleotide/oligosaccharide Binding) that bind POT1 to single-stranded DNA,[23] which increase its affinity for single-stranded TTAGGG region of telomeric DNA. POT1 helps form the telomere-stabilizing D-loop.[12] POT1 prevents the degradation of this single stranded DNA by nucleases and shelters the 3' G-overhang.[8] POT1 suppresses ATR-mediated DNA repair.[6] Humans only have a single POT1, whereas mice have POT1a and POT1b.[24] POT1a inhibits DNA damage repair at the telomere, whereas POT1b regulates the length of telomeric single-stranded DNA.[12]
- CST Complex limits excessive telomere elongation by telomerase.[6] The gene which encodes for TPP1 (ACD) is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I.[27]
- TIN2 (TRF1- and TRF2-Interacting Nuclear Protein 2) TIN2 is a stabilizing protein that binds to TRF1, TRF2, and the TPP1-POT1 complex.[28] thereby bridging units attached to double-stranded DNA and units attached to single-stranded DNA.[7] TIN2 seems to affect telomerase activity, without being in direct contact with that enzyme.[26]
Repression of DNA repair mechanisms
There are two main DNA-damage-signaling pathways that shelterin represses: the
TIN2 and TRF2 independently block accumulation of the DNA repair enzyme PARP1 at telomeres.[9]
The structure of the T-loop may prevent NHEJ.[1] 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.[7]
Species differences
At least four factors contribute to telomere maintenance in most eukaryotes:
Plants contain a variety of telomere-protecting proteins which can resemble either shelterin or the CST Complex.[32]
The fruit fly Drosophila melanogaster lacks both shelterin and telomerase, but instead uses retrotransposons to maintain telomeres.[33]
Non-telomeric functions of shelterin proteins
TIN2 can localize to
RAP1 regulates transcription and affects NF-κB signaling.[11]
See also
- TERRA (biology)
- CST Complex
References
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