Interactions of the BRCA1-BRCT domain with ABRAXAS1, BRIP1, and CtIP have distinct functions and serve as regulatory components of the initial steps of homologous recombination DNA damage repair

Abstract

DNA double strand breaks (DSBs) form a threat to genome integrity, as they are perceived to be the most dangerous type of DNA damage. Repairing DSBs correctly is important, and several mechanisms are in place to ensure this occurs in a precise and tightly regulated manner. Homologous recombination (HR) is one of the main pathways through which DSBs are repaired and uses a homologous sequence as a template for repair. Importantly, this makes HR an error-free process. Germline mutations in breast cancer type 1 susceptibility protein (BRCA1) are often detected in early-onset breast cancer patients. BRCA1 is known to play many roles in HR, but not all of its specific contributions have been elucidated. The BRCA1-BRCT domain has been reported to be essential for HR function of BRCA1. Three proteins are known to interact with one specific residue of the BRCA1-BRCT domain, namely ABRAXAS1, BRIP1, and CtIP. These three main interactions are each thought to contribute to different steps of the HR pathway and are also known to interact with other factors to form the BRCA1-A, BRCA1-B, and BRCA1-C complex, respectively. First of all, the interaction between BRCA1-BRCT and ABRAXAS1 is considered to decrease HR activity, as it tightly regulates the recruitment of components necessary for DNA end resection. Secondly, the BRCA1-CtIP interaction is reported to increase HR activity by enhancing CtIP function during the initiation of DNA end resection. Lastly, it remains to be determined whether the interaction between BRCA1-BRCT and BRIP1 increases HR activity or leaves it unaffected. Although not all individual interactions are deemed to be necessary, the versatile roles of the interactions with BRCA1-BRCT combined make it so that this domain plays a central part in the initiation of HR.