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eSymposia | Genomic Stability and DNA Repair


Dysregulation of HR leads to lethality at the G2/M transition in human cells


Sep 21, 2020 12:00am ‐ Sep 21, 2020 12:00am

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Dysregulation of HR leads to lethality at the G2/M transition in human cells Mélissa Thomas1, Stéphane Koundrioukoff2, Quentin Delacour2, Michelle Debatisse2, Olivier Gavet2, Bernard S. Lopez1 and Josée Guirouilh Barbat1 1SiNG team, INSERM U1016, CNRS UMR8104, Cochin Institute, Paris, France 2Genome Integrity and Cancer, CNRS UMR9019, Gustave Roussy Institute, Villejuif, France Homologous recombination (HR) is involved in repairing DNA double strand breaks, the most toxic type of DNA lesions, and in recovering stalled or broken replication forks. Rad51, BRCA1 and BRCA2 are key HR proteins. I have shown that inhibiting HR, as well as overexpressing Rad51, is lethal in human cells but that a very few clones are still able to survive. Additionally, it’s important to note that HR genes are often mutated in many cancers such as colon, prostate, pancreatic, lung and gastric cancers. More particularly, BRCA2 and BRCA1 mutations are responsible for 90% of hereditary cases of breast cancer as well as most hereditary ovarian cancer cases. This raises the question of how do cancer cells manage to survive despite a dysregulation of HR, which should be lethal. My project aims to identify when, how and why do HR-dysregulated cells die, as well as to understand how a few cells manage to survive. My results so far have shown that HR-dysregulated cells are accumulating in late G2, where they most likely die from G2/M checkpoint-triggered apoptosis. Previous to that, replication seems to be difficult in these cells, which exhibit a disrupted S phase. An analysis of the TCGA database has revealed that most HR-mutated cancers are also mutated in a gene involved in the G2/M checkpoint or in fork recovery. This work should allow us to identify potential therapeutic targets for treating HR-mutated cancers.

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