8^th Annual Pharma Middle East Congress

Biography

Biography: Jean-Baptiste Vannier

Abstract

RTEL1 (Regulator of TElomere Length 1) is an essential DNA helicase that plays a critical role in genome stability and is a potential tumour suppressor identified as a susceptibility locus for glioma. RTEL1 is also mutated in a severe form of Dyskeratosis Congenita, Hoyeraal-Hreidarsson syndrome (HHS), which is characterized by bone marrow failure, immunodeficiency and developmental defects. HHS-causing mutations have also been identified in several telomerase components including, DKC1, CTC1 and TIN2. RTEL1 deficiency reflects a defect in dismantling toxic recombination intermediates but how this function contributes to telomere dysfunction and tumourigenesis was not known. Using biochemistry and mouse genetics, I established that RTEL1 utilizes its D-loop disruption activity to promote telomere loop disassembly, which is essential for preventing catastrophic telomere processing by the SLX1-SLX4 nuclease complex and loss of the telomere as a circle. RTEL1 has a second function at telomeres in unwinding telomeric G-quadruplex DNA structures that is required to facilitate telomere replication and suppress telomere fragility. RTEL1 executes these two functions through different binding activities mediated via an interaction with PCNA and/or telomeric factor TRF2. Although RTEL1-Replisome deficient mice are viable, loss of the RTEL1-Replisome interaction significantly accelerates the onset of tumourigenesis and predisposes to medulloblastomas in p53 deficient mice. Collectively, the data revealed that RTEL1 plays a critical role genome stability and tumour avoidance and elucidates the mechanism of action of RTEL1 in cells and propose why patients with RTEL1 mutations suffer severe telomere defects.