A mitotic DNA damage response is essential in BRCA1/BRCA2-deficient cells

The breast cancer susceptibility genes BRCA1 and BRCA2, are potent tumor suppressors. The loss of these genes causes profound genomic instability due to their role in homologous recombination and replication fork management. While BRCA-deficient tumors initially respond well to standard-of-care therapies, such as cisplatin and PARP inhibitors (PARPi), tumors invariably acquire resistance to these agents and do recur, leaving patients with very few therapeutic options. It is therefore imperative that we identify new genetic vulnerabilities caused by BRCA1/2 mutations, as a means to identify new therapeutic targets for BRCA-deficient tumors. In my presentation, I will discuss our recent efforts in mapping genome maintenance pathways using genome-scale CRISPR/Cas9 screens in human cells, including BRCA synthetic lethality screens. I will focus much of my presentation on CIP2A, which we find to be essential for the viability of BRCA-deficient cells. Surprisingly, CIP2A is not a canonical DNA repair factor but it rather acts during mitosis to promote the segregation of broken chromosomes that accumulate BRCA-deficient cells due to defective DNA replication. This work not only highlights CIP2A as a candidate target for the development of new synthetic lethal therapies for BRCA-deficient malignancies, but it also highlights the importance of the DNA damage response during mitosis, which remains grossly understudied.

Daniel Durocher is a Senior Investigator and Biomedical Program Director at the Lunenfeld-Tanenbaum Research Institute. He is also a Professor in the Department of Molecular Genetics at the University of Toronto. Dr. Durocher’s overarching interest lies in understanding how cells maintain genome integrity, with an emphasis on the detection, signaling and repair of DNA double-strand breaks. He is also keenly interested in exploiting the concept of synthetic lethality for cancer therapy and as part of these efforts, he co-founded Repare Therapeutics, an early-state drug development company aiming to develop new drugs based on this idea. Among the prizes, awards and honors received by Dr. Durocher in recent years, particularly notable is the 2016 Paul Marks Prize for cancer research awarded by Memorial Sloan Kettering.

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