DNA double-strand break repair pathway choice and cancer

Abstract

Since DNA double-strand breaks (DSBs) contribute to the genomic instability that drives cancer development, DSB repair pathways serve as important mechanisms for tumor suppression. Thus, genetic lesions, such as BRCA1 and BRCA2 mutations, that disrupt DSB repair are often associated with cancer susceptibility. In addition, recent evidence suggests that DSB "mis-repair", in which DSBs are resolved by an inappropriate repair pathway, can also promote genomic instability and presumably tumorigenesis. This notion has gained currency from recent cancer genome sequencing studies which have uncovered numerous chromosomal rearrangements harboring pathological DNA repair signatures. In this perspective, we discuss the factors that regulate DSB repair pathway choice and their consequences for genome stability and cancer.

Keywords: 53BP1–BRCA1; DNA double strand break; DNA ends; Microhomology-mediated end joining; Repair pathway choice; Resection.

Figure 1. DSB repair pathway choices and their regulation

The three major modalities of DSB repair (NHEJ, HDR and MMEJ/SSA) are depicted. NHEJ can process ligatable DNA ends but is inhibited by modified/damaged DNA ends. In contrast, MMEH or HDR, which both initiate by resection, can process both types of ends. Competition between NHEJ and HDR takes place directly on DNA ends between KU and MRN, as well as in the vicinity of the break between 53BP1 and BRCA1. HDR is not operating in G1 due to the absence of a sister chromatin as homologous template. NHEJ in S-phase is toxic. See text for details.