Fork Protection and Therapy Resistance in Hereditary Breast Cancer

Abstract

The BRCA-Fanconi anemia (FA) pathway preserves the genome and suppresses cancer and is a main determinant of chemotherapeutic efficacy. The hereditary breast cancer genes BRCA1 and BRCA2 function in DNA double-strand break repair mediating distinct steps of homologous recombination (HR). More recently, independent of DNA repair, functions in the replication stress response have come to light, providing insight as to how the BRCA-FA pathway also balances genome preservation with proliferation. The BRCA-FA proteins associate with the replisome and contribute to the efficiency and recovery of replication following perturbations that slow or arrest DNA replication. Although the full repertoire of functions in the replication stress response remains to be elucidated, the function of BRCA1 and BRCA2 in protecting stalled replication forks contributes along with HR to the sensitivity of BRCA-associated tumors to chemotherapy. Moreover, chemoresistance evolves from restoration of either HR and/or fork protection. Although mechanisms underlying the restoration of HR have been characterized, it remains less clear how restoration of fork protection is achieved. Here, we outline mechanisms of "rewired" fork protection and chemotherapy resistance in BRCA cancer. We propose that mechanisms are linked to permissive replication that limits fork remodeling and therefore opportunities for fork degradation. Combating this chemoresistance mechanism will require drugs that inactivate replication bypass mechanisms.

Figure 1

Model of the mechanisms and potential consequences of fork protection in BRCA1/2 -deficient cells. (A) In wild-type (WT cells), when replication stress (represented by X) is encountered in the course of cancer therapy, there is a reversal of replication forks, and the protection of nascent DNA in a BRCA1-, BRCA2-, and Rad51-dependent manner, that limits resection by nucleases such as MRE11, CtIP, and EXO1. Following TS or recombination-based restart, the replication fork is restarted, thereby conferring chemo-resistance. In absence of BRCA1/2, (B) Rad51 is no longer stabilized on reversed forks, allowing access of nucleases to nascent DNA, resulting in extensive degradation and chemosensitivity. (C) Extensive nascent cell degradation can be avoided by either loss of fork degradation factors or gain in stabilization factors that will allow forks to restart via template switch (TS) and confer chemotherapy resistance if viability is not also compromised. (D) Loss of fork reversal will limit fork degradation if translesion synthesis (TLS) is active at the fork and gaps generated by repriming reactions are avoided.