Understanding the role of the BRCA pathway in DNA-protein crosslink repair

Abstract

The DNA damage response (DDR) is comprised of a complex network of biochemical pathways that has evolved to maintain genomic stability. Two key components of this system are BRCA1 and BRCA2 (BRCA). Importantly, BRCA deficient cells are highly sensitive to PARP inhibitors, which prevent the dissociation of PARP from DNA, generating a DNA-protein crosslinks (DPCs).  

DPCs represent a remarkably understudied area of DNA damage, but one protein well characterised to facilitate the repair of DPCs is SPRTN. Here, we demonstrate that BRCA1 and BRCA2 deficient cells are sensitive to two distinct DPC inducing agents. Furthermore, we also investigate links between both BRCA1 and BRCA2 and the DPC processing protease SPRTN. We also investigate repair pathway choice in response to these two agents and their ability to activate the innate immune response.  

In conclusion, our results provide evidence that BRCA deficient cells are highly sensitive to other forms of DPCs, and not just PARP adducts, and begin to elucidate the DPC repair pathway responsible for their processing. This provides rationale for novel combination therapies for BRCA deficient tumours, exploiting this vulnerability.