Pathology Presents: The Fanconi Anemia-BRCA Pathway and Cancer
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Toshi Taniguchi, MD, PhD
Divisions of Human Biology and Public Health Sciences
Fred Hutchinson Cancer Research Center
- Faculty Sponsor
Kiran K. Dhillon, PhD
The Fanconi Anemia-BRCA Pathway and Cancer
The Fanconi anemia-BRCA pathway has emerged as an important pathway in cancer biology. Fanconi anemia (FA) is a rare genetic disease characterized by chromosomal instability, cancer-susceptibility and cellular sensitivity to interstrand DNA crosslink (ICL)-inducing agents. The FA proteins and breast/ovarian cancer susceptibility proteins, BRCA1 and BRCA2, cooperate in a common pathway required for cellular resistance to ICL-inducing agents. This pathway is called the FA-BRCA pathway or FA pathway. The main function of the pathway is to coordinate multiple DNA repair mechanisms during ICL repair. Inactivation of this pathway in cancer cells can lead to sensitivity to anti-cancer ICL-inducing agents, such as cisplatin, while reactivation of this pathway is implicated in acquired resistance to ICL-inducing agents. Therefore, inhibition of the pathway is an attractive therapeutic strategy to overcome DNA-crosslinker resistance of tumor cells. In this talk, I will introduce what the FA-BRCA pathway is and how this pathway is inactivated in human cancer. I will also mention our finding that secondary BRCA1/2 mutations, which restore normal function of BRCA1/2 proteins, are involved in acquired drug resistance of BRCA1/2-mutated cancer. I will also discuss our recent findings about the regulation of the FA core complex. In addition, I’d like to mention a novel cellular pathway called the DGCR8-mediated UV response pathway. DGCR8 is an RNA-binding protein playing a critical role in microRNA biogenesis. We recently found that DGCR8 also plays an unexpected role in DNA repair of UV-induced lesions and have proposed this pathway.