University of Cambridge > > MRC LMB Seminar Series > The function and execution of RTEL1 activities at vertebrate telomeres

The function and execution of RTEL1 activities at vertebrate telomeres

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

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.

Tell a friend about this talk:

This talk is included in these lists:

Note that ex-directory lists are not shown.


© 2006-2024, University of Cambridge. Contact Us | Help and Documentation | Privacy and Publicity