QBI presents a seminar with Dr. Ludovic Deriano, the Research Director and Head of the Genome Integrity, Immunity and Cancer Unit at the Institut Pasteur in Paris.

Dr. Deriano's research primarily focuses on understanding how lymphoid cells maintain DNA integrity and prevent genomic instability and transformation. 

Talk Title: Genetic Adaptation Mapping to BRCA1 and BRCA2 Loss Reveals Divergent Vulnerabilities and Therapeutic Opportunities

Mutations in the tumor suppressor genes BRCA1 and BRCA2 drive breast, ovarian, prostate, and other cancers, and render cells hypersensitive to PARP inhibitors. However, how BRCA-deficient cells survive and proliferate despite severely impaired DNA repair capacity and high genomic instability remains largely unexplored.

To investigate this long-standing paradox, Dr. Deriano's group developed a genetic adaptation screening platform to identify genes that enable cells to tolerate the acute loss of BRCA1 or BRCA2. Unlike previous studies that relied on pre-adapted cellular models—such as tumor-derived cell lines or clonally selected knockouts—they used mouse embryonic stem cells engineered for rapid (within hours) depletion of endogenous BRCA1 or BRCA2. This experimental design allowed them to trace the adaptation routes that make initially healthy cells permissive to BRCA1 and BRCA2 deficiencies. Genome-scale CRISPR-Cas9 screens were performed under normal conditions, as well as in the presence of etoposide (a Topoisomerase II inhibitor) or olaparib (a PARP inhibitor), across multiple time points—yielding 28 distinct datasets. The full isogenicity of their system enabled direct comparison of genetic interactions in BRCA1- versus BRCA2-deficient cells, based on both magnitude and sign (positive or negative effect). This analysis revealed hundreds of genes with either shared, specific, or opposing roles in BRCA1- and BRCA2-deficient contexts. Notably, they identified 20 genes with opposite effects: their loss was lethal in BRCA1-deficient cells but enhanced the fitness of BRCA2-deficient cells. Among these, six genes encode a protein complex (referred to here as Complex X), which is involved in DNA metabolism during replication and cell division.

In this talk, Dr.Deriano will present his group's adaptation screening platform and highlight its potential to uncover novel synthetic viable and synthetic lethal interactions in BRCA1- and BRCA2-deficient cells, with important implications for developing tailored therapeutic strategies in BRCA1 and BRCA2-mutated cancers. He will also discuss their mechanistic work on Complex X, shedding light on its surprising dual role in modulating cell fitness in BRCA1 versus BRCA2 deficiency.