Abstract PR05: Distinct BRCA1- and BRCA2-specific functions at stalled replication forks: Clinical implications for differences between BRCA1 and BRCA2 mutation-driven cancer

BRCA1 and BRCA2 are tumor suppressor genes, and germ line mutations in these two genes increase the risk of breast cancer. Both BRCA1 and BRCA2 are required for stabilization and repair of stalled replication forks. Stalled forks, when not resolved, lead to mutations, or collapse into double strand breaks (DSBs). Both outcomes result in what is commonly referred to as replication stress (RS), which, when chronic, is a driving force behind cancer development. However, it is not clear what are the differences, if any, between BRCA1 and BRCA2 dependent stabilization and repair of stalled replication fork. Getting a better understanding of how these two proteins help suppress RS will not only help reveal how they contribute to breast cancer suppression, but will also give us an insight into the differences in the spectrum of cancers in BRCA1 and BRCA2 mutation carriers. Such knowledge is also critical in designing better therapeutic options for BRCA1 and BRCA2 specific mutation carriers.Here we report a novel role for BRCA2 in suppressing RS by regulating RPA (replication protein A) accumulation on ssDNA (single stranded DNA) at stalled forks. More specifically, we show that BRCA2 is required for efficient turnover of RPA, and in absence of BRCA2 there is "persistent" accumulation of mostly un-phosphorylated RPA (at S33, T21 and S4/S8) at stalled forks. Furthermore, inefficient turnover of RPA in absence of BRCA2 not only results in fork collapse, as marked by increased accumulat...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Replication Stress: Oral Presentations - Proffered Abstracts Source Type: research