Shelterin
Shelterin (also called telosome) is a protein complex known to protect mammalian telomeres from DNA repair mechanisms, as well as regulate telomerase activity. In mammals and other eukaryotes, telomeric DNA consists of double- and single-stranded TTAGGG repeats and a single-stranded, G-rich overhang. Subunits of shelterin bind to these regions and induce the formation of a t-loop, a cap structure that deters DNA-damage-sensing machinery from mistakenly “repairing” telomeres. The absence of shelterin causes telomere uncapping and thereby activates damage-signaling pathways that may lead to non-homologous end joining (NHEJ), homology directed repair (HDR),[1] senescence, or apoptosis.[2]
Subunits
Shelterin has six subunits: TRF1, TRF2, POT1, RAP1, TIN2, and TPP1.[3] They can operate in smaller subsets to regulate the length of or protect telomeres.
- TRF1 (Telomere Repeat Factor 1): TRF1 is a homodimeric protein[4] that binds to the double-stranded TTAGGG region of the telomere. It may recruit PINX1 to inhibit telomere elongation by telomerase.[2]
- TRF2 (Telomere Repeat Factor 2): TRF2 is a homodimeric protein[4]that binds to the double-stranded TTAGGG region of the telomere and prevents the recognition of double-strand DNA breaks.[5]
- POT1 (Protection of Telomere 1): POT1 contains oligonucleotide/oligosaccharide binding folds, which increase its affinity for single-stranded TTAGGG region of telomeric DNA. POT1 prevents the degradation of this single stranded DNA by nucleases and shelters the G-overhang.[3]
- RAP1 (Repressor / Activator Protein 1): RAP1 is a stabilizing protein associated with TRF2.
- TIN2 (TRF1- and TRF2-Interacting Nuclear Protein 2): TIN2 is a stabilizing protein that binds to the TPP1-POT1 complex, TRF1, and TRF2,[6] thereby bridging units attached to double-stranded DNA and units attached to single-stranded DNA.[2]
- TPP1 (TINT1, PTOP, PIP1): TPP1 is a protein associated with POT1. The loss of TPP1 leads to impaired POT1 function.[2]
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.[4] 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.
The structure of the t-loop may prevent NHEJ.[4] 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.[2]
See also
References
- ↑ Rodriguez, Raphaël, Sebastian Müller, Justin A. Yeoman, Chantal Trentesaux, Jean-Françios Riou, and Shankar Balasubramanian. “A Novel Small Molecule That Alters Shelterin Integrity and Triggers a DNA-Damage Response at Telomeres.” Journal of the American Chemical Society 130 (2008): 15758-59. doi: 10.1021/ja805615w.
- ↑ 2.0 2.1 2.2 2.3 2.4 Palm, Wilhelm, and Titia de Lange. “How Shelterin Protects Mammalian Telomeres.” Annual Reviews 42 (2008): 301-34. doi: 10.1146/annurev.genet.41.110306.130350.
- ↑ 3.0 3.1 Xin, Huawei, Dan Liu, and Zhou Songyang. “The telomere/shelterin complex and its functions.” Genome Biology 9 (2008): 232.
- ↑ 4.0 4.1 4.2 4.3 de Lange, Titia. “How Shelterin Solves the Telomere End-Protection Problem.” Cold Spring Harbor Symposia on Quantitative Biology 75 (2010): 167-77. doi: 10.1101/sqb.2010.75.017.
- ↑ Choi, Kyung H., Amy S. Farrell, Amanda S. Lakamp, and Michel M. Ouellette. “Characterization of the DNA binding specificity of Shelterin complexes.” Nucleic Acids Research 39 (2011): 9206-23. doi 10.1093/nar/gkr665.
- ↑ Takai, Kaori K., Sarah Hooper, Stephanie Blackwood, Rita Gandhi, and Titia de Lange. “In Vivo Stoichiometry of Shelterin Components.” Journal of Biological Chemistry 285 (2010): 1457-67. doi: 10.1074/jbc.M109.038026.