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Sofiane Yacine Mersaoui (U. Laval) Role of R-loops in resistance to PARP inhibitors
Le CERMO-FC a le plaisir de vous inviter à la présentation du Dr Sofiane Yacine Mersaoui, Stagiaire post-doctoral dans le laboratoire du Pr Jean-Yves Masson à l’Université Laval. Ses travaux de recherche vous seront présentés Jeudi 12 mai 2022 à 12h00.
CERMO-FC is pleased to invite you to the presentation of Dr Sofiane Yacine Mersaoui, post-doctoral fellow in the laboratory of Pr Jean-Yves Masson at Laval University. His research work will be presented to you on Thursday May 12, 2022 at 12:00 p.m.
Role of R-loops in resistance to PARP inhibitors
Abstract: Human DNA is constantly challenged by exogenous and endogenous events which cause multiple types of damage such as single and double-strand breaks (DSB). DSBs are one of the most deleterious DNA lesions, as unrepaired DSBs result in loss of genetic information, chromosome rearrangements and genome instability. Homologous recombination is a highly conserved mechanism that repairs DSBs faithfully. Breast cancer susceptibility genes 1/2 (BRCA1/2) are two key proteins involved in homologous recombination. When mutated, these genes are associated with breast cancer development which is the most common form of cancer among Canadian women. PARP inhibition is one of the promising clinical strategies to kill such HR-deficient tumors by synthetic lethality, the concept by which the combination of two or more independently viable genetic defects results in cell death.
Despite their success, PARP inhibitor use can lead to resistance through HR restoration. Importantly, the exact mechanism driving HR recovery remains an ongoing question in the DNA repair field. Herein, we uncovered a new relation between R-loop metabolism and PARP inhibitor resistance in BRCA2-mutated cells. R-loops are RNA:DNA hybrids that accumulate during many cellular processes, including transcription and replication. Herein we identify a function for PARP-1 in R-loops metabolism; Remarkably, both PARP-1 depletion or inhibition using small-molecule inhibitors result in R-loops accumulation at specific loci. Second, using a siRNA-based screen in Hela-BRCA2 deficient cells, we reveal a functional role of various R-loops factors as suppressors of PARP inhibition. Thus, mutation of these factors such as SETX results in a robust resistance to PARP inhibition by restoring HR and RAD51 foci formation leading to cell growth recovery. Altogether, our work has direct implications to monitor the effectiveness of PARP inhibition in clinical settings.
Biography: With a biotechnology engineer degrees (2001-2006), Dr Mersaoui joined a pharmaceutical R&D lab where he developed and formulated new drugs in a multidisciplinary team. During his master degree (2008-10) at the University of Paris, he explored many model organisms such as fungi and bacteria, and focus his study on DNA damage repair (DDR). His work was rewarded by the “Société Française de Radioprotection”, and published in Radioprotection (2010) and DNA repair (2013). For the Ph.D program (2011-17), He joined one of the most important laboratories studying telomeres in Canada which is driven by Dr. Wellinger (Université de Sherbrooke). He investigated the role of telomeres in preventing aging and DNA damage activation, and demonstrated a new regulatory mechanism by which telomeres can be protected from resection and secure chromosome maintenance. During his training, he obtained a faculty scholarship, and presented his work in more than ten international meetings. Overall, his PhD work was published in Current Genetics (2019), NAR (2018), and Microbial Cell (2015).
Then, he pursued his postdoc training at the McGill University under the supervision of Dr. Stéphane Richard at the Lady Davis Institute (2017-19). His work was focused on how protein arginine methyltransferase (PRMT) maintains genome stability. Conjointly with Dr. Jean-Yves Masson from University Laval, they identified DDX5 as a new substrate of PRMT5. They discovered that DDX5, XRN2 and PRMT5 regulate R-loops metabolism to prevent genome instability. Published in EMBO Journal (2019), this work allowed him to secure a PDF FRQS scholarship. Afterward, they conducted a genomic study to identify the unique and shared roles of DDX5, XRN2, and PRMT5 in DNA/RNA hybrid regulation, published in Life Science Alliance (2020), and honoured at the Lady Davis Institute as a paper of the month. In 2020, Dr Mersaoui moved to University Laval to continue this great collaboration with Dr. Masson’s team and focused on the role of R-loops in DDR, and in response to PARP inhibition. Their initial work shed light on the pivotal role of DDX5 in clearing R-loops at DSBs to avoid chromosomal deletions and genome instability (NAR Cancer, 2020).
Un évènement organisé dans le cadre des Pause-conférences du CERMO-FC
An event organized as part of the Pause-conférences of CERMO-FC
