The function and execution of RTEL1 activities at vertebrate telomeres

Add to your list(s) Download to your calendar using vCal

• Dr Simon Boulton, DNA damage Response Laboratory, London Research Institute
• Friday 27 June 2014, 16:15-18:00
• Max Perutz Lecture Theatre, Medical Research Council (MRC) (MRC Laboratory of Molecular Biol.

If you have a question about this talk, please contact Scientific Meetings Co-ordinator.

Regulator of telomere length 1 (RTEL1) is an essential Fe-S dependent DNA helicase that regulates homologous recombination, disassembles telomere (T)-loops and suppresses telomere fragility to maintain the integrity of the genome. The emergence of RTEL1 variants that confer increased susceptibility to high-grade Glioma, Astrocytomas and Glioblastomas has highlighted the importance of RTEL1 in human cancers. Mutations in RTEL1 have also been implicated in Hoyerall-Hreidarsson syndrome (HHS), a severe form of the bone marrow failure and cancer predisposition disorder, Dyskeratosis Congenita. We previously reported that RTEL1 binds to the replisome via a PIP -box dependent interaction with PCNA . Disruption of the RTEL1 -PCNA interaction in mice compromised genome-wide and telomere replication, and accelerated the onset of tumourigenesis in p53 deficient animals. Unexpectedly, the RTEL1 -PCNA interaction was found to be dispensable for T-loop disassembly, which suggested the existence of a distinct mechanism for recruiting RTEL1 to telomeres. Indeed, we have discovered that RTEL1 is recruited to telomeres via an S-phase specific interaction with the shelterin component TRF2 . We proceeded to identify a single point mutation within TRF2 that abrogates the interaction with RTEL1 and phenocopies the Rtel1 null phenotype. Finally, we demonstrated that the RTEL1 -TRF2 interaction is compromised by the R1264H mutation in RTEL1 , which is causal for HHS and exists at a carrier frequency of 1 in 100 within the Ashkenazi Jew population. These results define a clinically important interaction between RTEL1 and TRF2 , which is critical for the timely disassembly of T-loops during S-phase of the cell cycle.

• Barber LJ, Youds JL, Ward JD, McIlwraith M, O’Neil NJ, Petalcorin MIR , Collis SJ, Martin JS, Cantor SB, Auclair M, Tissenbaum H, West SC, Rose AM & Boulton SJ (2008). RTEL1 maintains genomic stability by suppressing homologous recombination. Cell. 135:261-71. • Youds JL, Mets D, McIlwraith MJ, Martin JS, Ward JD, O’Neil NJ, Rose AM, West SC, Meyer B & Boulton SJ (2010) RTEL -1 enforces meiotic crossover interference and homeostasis. Science, 327:1254-8. • Vannier J-B, Petalcorin MIR , Pavicic-Kaltenbrunner V, Ding H & Boulton SJ (2012). RTEL1 dismantles T-loops and counteracts telomeric G4-DNA to maintain telomere integrity. Cell 149:795-806. • Vannier JB, Sandhu S, Petalcorin MIR , Wu X, Nabi Z, Ding H & Boulton SJ (2013). RTEL1 is a replisome-associated helicase that promotes genome and telomere replication. Science, 342: 239-242. • Vannier J-B, Sarek G & Boulton SJ (2014). RTEL1 : functions of a disease-associated helicase. Trends in Cell Biology, 10.1016/j.tcb.2014.01.004.

This talk is part of the MRC LMB Seminar Series series.

This talk is included in these lists:

• All Talks (aka the CURE list)
• Biology
• CCC talks for website
• Cambridge Immunology
• Centre for Health Leadership and Enterprise
• Liam
• Life Sciences
• Life Sciences
• ME Seminar
• MRC LMB Seminar Series
• Max Perutz Lecture Theatre, Medical Research Council (MRC) (MRC Laboratory of Molecular Biol
• Neurons, Fake News, DNA and your iPhone: The Mathematics of Information
• cri
• my_list
• other talks
• rc781

Note that ex-directory lists are not shown.