Shelter

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Shelterin (from English shelter , dt. 'Schutz, Obdach') is a protein complex at the ends of the telomeres of chromosomes and serves to protect and regulate the length of the telomeres.

properties

Shelterin is found in most eukaryotes . In various yeasts (in Schizosaccharomyces pombe , but not Saccharomyces cerevisiae ) and in all mammals , shelterin consists of six proteins . By binding to the telomeres, a remodeling of the telomeres through a DNA repair of free ends of DNA and a fusion of two chromosome ends is avoided.

Shelter in mammals

The Shelterin protein complex consists of TRF1, TRF2, RAP1, TIN2, POT1 and TPP1 .

TRF1

TRF1 ( Telomeric Repeat binding Factor 1 ) and TRF2 bind to telomeres independently of one another and together prevent their extension by telomerase . TRF1 binds helicases when the telomeres are elongated. In addition to the proteins of the shelterin, tankyrase ( PARP modification of TRF1 , protection, dissolution of the complex), PINX1 (telomerase inhibitor), ATM ( TRF1 - phosphorylation , regulation of telomere length), Ku70 / 80 ( homology-directed repair - bind to TRF1 ) . Inhibition), FBX4 / Nucleostemin ( TRF1 - ubiquitination and degradation), PIN1 / GNL3L ( TRF1 - folding , dimerization ).

TRF2

TRF2 prevents activation of the protein Ataxia telangiectatica mutated (ATM), which initiates DNA repair in the event of a double-strand break . TRF2 is involved in repairs to telomeres . An TRF2 in addition to the proteins of the Shelterins also bind Apollo (at the end of single-stranded), the ORC complex (Telomerschutz), ATM (inhibited by binding to TRF2 ), the MRE11 complex (at the end of single-stranded), XPF-ERCC1 (at the end of single-stranded ), WRN / FEN1 (chromosomal replication, inhibition of T-SCE ), Ku70 / 80 (HDR inhibition parallel to RAP1 , suppression of t-circles ), PNUTS (regulation of telomere length) and MCPH1 (telomere protection). By binding TRIP6 / LPP , TRF2 can be modified by the arginine methylase PRMT1 .

TIN2

TIN2 binds telomere single-strand binding proteins to the telomeres. TIN2 ( TRF1 Interacting Nuclear Factor 2 ) binds to TRF1 , TRF2 and POT1 .

POT1

POT1 ( Protector Of Telomeres 1 ) binds to single-stranded telomeres and prevents activation of the protein Ataxia telangiectasia and Rad3 related (ATR, activated in case of double-strand breaks) by binding . While humans only have POT1 , mice have POT1a and POT1b .

RAP1

The RAP1 ( repressor / activator protein 1 ) binds to TRF2 and increases its activity. Regardless of the shelterin complex, RAP1 also regulates transcription and is involved in the NF-κB signaling pathway.

TPP1

TPP1 (synonymous TINT1, PTOP, PIP1 - POT1-TIN2 organizing protein ) binds to POT1 . When the telomeres are elongated , TPP1 binds the telomerase to the telomeres. A deletion of TPP1 leads to an ATR -mediated DNA repair. In addition to the proteins of the shelterin, TPP1 and POT1 also bind to ATR .

Web links

Individual evidence

  1. ↑ R. Diotti, D. Loayza: Shelterin complex and associated factors at human telomeres. In: Nucleus (Austin, Tex.). Volume 2, number 2, 2011 Mar-Apr, ISSN  1949-1042 , pp. 119-135, doi : 10.4161 / nucl.2.2.15135 , PMID 21738835 , PMC 3127094 (free full text).
  2. ↑ MP Longhese, S. Anbalagan, M. Martina, D. Bonetti: The role of Shelterin in Maintaining telomere integrity. In: Frontiers in bioscience (Landmark edition). Volume 17, 2012, ISSN  1093-4715 , pp. 1715-1728, PMID 22201831 .
  3. ↑ T. Miyoshi, J. Kanoh, M. Saito, F. Ishikawa: Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length . In: Science . 320, No. 5881, 2008, pp. 1341-1344. doi : 10.1126 / science.1154819 . PMID 18535244 .
  4. ↑ a b c Nandakumar J1, Cech TR: Finding the end: recruitment of telomerase to telomeres . In: Nature Reviews Molecular Cell Biology . 14, No. 2, 2013, pp. 69-82. doi : 10.1038 / nrm3505 . PMID 23299958 . PMC 3805138 (free full text).
  5. ↑ a b c d e Sfeir A: Telomeres at a glance . In: Journal of Cell Science . 125, No. Pt 18, 2012, pp. 4173-4178. doi : 10.1242 / jcs.106831 . PMID 23135002 .
  6. ↑ a b M. Rajavel, MR Mullins, DJ Taylor: Multiple facets of TPP1 in telomere maintenance. In: Biochimica et Biophysica Acta . Volume 1844, number 9, September 2014, ISSN  0006-3002 , pp. 1550–1559, doi : 10.1016 / j.bbapap.2014.04.014 , PMID 24780581 , PMC 4112156 (free full text).
  7. ↑ a b c d e f Diotti R1, Loayza D: Shelterin complex and associated factors at human telomeres . In: NUCLEUS . 2, No. 2, 2011, pp. 119-135. doi : 10.4161 / nucl.2.2.15135 . PMID 21738835 . PMC 3127094 (free full text).
  8. ↑ a b O'Connor MS1, Safari A, Xin H, Liu D, Songyang Z: A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly . In: Proceedings of the National Academy of Sciences of the United States of America . 103, No. 32, 2006, pp. 11874-11879. doi : 10.1073 / pnas.0605303103 . PMID 16880378 . PMC 1567669 (free full text).
  9. ↑ a b Kibe T1, Osawa GA, Keegan CE, de Lange T: Telomere protection by TPP1 is mediated by POT1a and POT1b . In: Molecular and Cellular Biology . 30, No. 4, 2010, pp. 1059-1066. doi : 10.1128 / MCB.01498-09 . PMID 19995905 . PMC 2815557 (free full text).
  10. ^ A b Martínez P1, Blasco MA: Role of shelterin in cancer and aging . In: Aging Cell . 9, No. 5, 2010, pp. 653-666. doi : 10.1111 / j.1474-9726.2010.00596.x . PMID 20569239 .
  11. ↑ J. Nandakumar, TR Cech: Finding the end: recruitment of telomerase to telomeres. In: Nature reviews. Molecular cell biology. Volume 14, number 2, February 2013, ISSN  1471-0080 , pp. 69-82, doi : 10.1038 / nrm3505 , PMID 23299958 , PMC 3805138 (free full text).
  12. ↑ E. Abreu, E. Aritonovska, P. Reichenbach, G. Cristofari, B. Culp, RM Terns, J. Lingner, MP Terns: TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo . In: Molecular and Cellular Biology . 30, No. 12, 2010, pp. 2971-2982. doi : 10.1128 / MCB.00240-10 . PMID 20404094 . PMC 2876666 (free full text).