Fumiko Esashi

Our research goal is to understand how genome integrity is maintained in proliferating cells, specifically through coordinating DNA damage repair and cell cycle progression. We are particularly interested in role of Cyclin-dependent kinases (CDKs), master regulators of cell proliferation, in DNA double strand break (DSB) repair.

We primarily focus on elucidating the role of CDK phosphorylation of the familial breast cancer susceptibility gene product, BRCA2, and its binding partners. The BRCA2 gene was originally identified through germ-line mutations that predispose individuals to the development of breast, ovarian and other cancers. BRCA2-defective cells exhibit spontaneous gross chromosomal instability phenotypes, and elevated sensitivity to ionizing radiation. BRCA2 is suggested to regulate DSB repair via its direct interaction with essential Rad51 recombinase, which plays central role in error-free DSB repair. We have previously revealed a regulatory role of CDKs in BRCA2 interaction with Rad51 during cell cycle and in response to DNA damage.

We aim to gain further insight into the roles of CDKs in DSB repair using a combination of biochemistry, molecular biology, genetics and proteomics. Specifically we will:

• Determine comprehensive role of CDK-dependent phosphorylations in BRCA2-RAD51 mediated DSB repair
• Identify associated repair pathways that are mediated by CDK-dependent BRCA2 phosphorylation
• Investigate role of other CDK substrates in the cell cycle regulated DSB repair.

De-regulation of CDK activities are often found in highly proliferating cancer cells. Therefore, understanding the role of CDKs in DNA repair is expected to illuminate a molecular mechanism of genome instability, and may ultimately identify new strategies for cancer diagnosis, prognostic tools and targets for cancer therapy.