L'implication des hybrides ADN : ARN et de la modification m6A des ARN dans la réparation des cassures double-brins de l'ADN

作者：Florian Saur · 发表于：HAL (Le Centre pour la Communication Scientifique Directe) · 年份：2023 · 研究领域：RNA modifications and cancer、Cardiac Structural Anomalies and Repair、Infective Endocarditis Diagnosis and Management

DNA double-strand breaks (DSBs) are considered to be one of the most toxic lesions in the cell that cause cancer. Importantly, recent works indicate that DSBs occur regularly in the genome in transcriptionally active genes. These DSBs require a specific repair pathway known as TC-DSBR (Transcription-Coupled DSB Repair), which remains poorly characterized. Indeed, only a handful of factors regulating this pathway have been identified, some of which are frequently mutated in cancer. It is therefore urgent to decipher the mechanisms of TC-DSBR, especially as certain genotoxic treatments used in chemotherapy (such as etoposide) have the particularity of preferentially inducing lesions in active genes. Recent works, including that of my team, indicates that DNA: RNA hybrids accumulate locally at the DSB and play a central role in TC-DSBR. My thesis work focused on understanding the biology of these hybrids. In particular, I was interested in their origin, which is still the subject of much debate. In addition, I studied their regulation, which is still poorly understood, with a particular interest in the m6A modification of RNAs in this process. Their regulation is indeed a crucial aspect in maintaining their homeostasis, as we know that the persistent presence of hybrids at DSBs is a source of genomic instability, resulting in cell death. Finally, I also studied the consequences of the presence of these hybrids on the three-dimensional reorganization of chromatin caused by the ap...