The talk will be followed by a refreshments in WTB Life Space, to which everyone is invited.
Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles DNA secondary structures in meiotic and mitotic cells1,2, an activity that is particularly important for DNA replication and maintain the integrity of chromosome ends3,4. The discovery of mutations in RTEL1 in Hoyerall-Hreidarsson syndrome (HHS), a severe form of the bone marrow failure and cancer predisposition disorder, Dyskeratosis Congenita, and the emergence of Rtel1 variants that confer heightened susceptibility to high-grade glioma, astrocytomas and glioblastomas has highlighted the importance of RTEL1 for genome stability. We previously reported that conditional inactivation of Rtel1 leads to rapid telomere dysfunction (telomere length heterogeneity, telomere loss, telomere fragility, telomere recombination and accumulation of extra-chromosomal telomere circles) as a result of the catastrophic nucleolytic processing of the telomere by the SLX1/4 resolvasome3. We recently discovered that the telomere dysfunction resulting from RTEL1 inactivation can be entirely suppressed by removal of telomerase5. While telomerase activity per se is dispensable for suppression of the Rtel1 telomere phenotype, blocking telomerase assembly or preventing its recruitment to the telomere is sufficient to mitigate the effects of deleting Rtel1. Our progress in understanding why telomerase is ‘toxic” to telomeres in the absence of RTEL1 will be presented.
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: 261-271.
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: 1254-1258.
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.
Margalef P, Borel V, Bellelli R Panier S & Boulton SJ (2017). Stabilization of reversed replication forks by telomerase drives telomere catastrophe. Cell. In revision.
About the lecture series:
Adam Neville as the Principal of the University of Dundee from 1978-1987. This lecture series was set up in recognition of Adam Neville’s key role in ensuring the survival of the Department of Biochemistry in the late 1970s at a time when its financial position was extremely precarious. This is one of SLS’s most prestigious named lectures.