Figure 4.

Regulation of DSB repair pathway choice by end resection. The 5’>3’ resection of DSB ends has emerged as a major node for regulation of DSB repair. The 4 major pathways – NHEJ, TMEJ, SSA, and HR – have distinct requirements for homology that determines the extent of resection required for successful pathway engagement. a) The first regulatory node is the recruitment of the 53BP1-Shieldin-CST/Polα anti-resection complex to DSB-associated chromatin. Recruitment of the anti-resection complex is antagonized by BRCA1. The 53BP1-Shielding-CST/Polα complex promotes NHEJ and antagonizes TMEJ, SSA, and HR. b) Initiation of end resection is mediated by the MRN complex and CtIP, the activity of which is regulated positively by ATM and CDK1/2, the latter of which restrains resection to the S/G2 phases of the cell cycle. This initial phase of end resection typically is limited to resection of <100bp, which is sufficient to inhibit Ku binding (thus impeding NHEJ) and promote TMEJ. c) Fast, processive resection involves recruitment of Exo1, DNA2, and/or BLM, nucleases that are also positively regulated by ATM and CDK1/2 phosphorylation. These factors can promote resection of 1000’s of bases, which facilitates homology search for SSA and HR. Whether extensively resected ends can be processed for TMEJ is currently unknown, but may involve degradation of the 3’ overhang.