PARG establishes a functional module with BRCA1-BARD1 that controls DNA repair pathway choice during gametogenesis

Abstract

ABSTRACTDuring meiosis, accurate chromosome segregation relies on the formation of programmed DNA double-strand breaks (DSBs). These are in turn repaired by homologous recombination (HR), generating physical attachments between the parental chromosomes called crossovers (COs). Fewer breaks yield recombinant outcomes, while CO-independent mechanisms are employed for repairing the majority of lesions. The balance between different repair pathways is crucial to ensure genome fidelity and to preserve its integrity. We show that Caenorhabditis elegans BRC-1/BRCA1-BRD-1/BARD1 and PARG-1/PARG form a complex in vivo, that is essential for accurate DNA repair in the germline. Contemporary depletion of BRC-1 and PARG-1 causes synthetic lethality due to reduced CO formation and impaired DSB repair, as evidenced by hindered RPA-1 removal and presence of aberrant chromatin bodies in diakinesis nuclei, whose formation depends on spo-11 function. These factors largely co-localize and undergo independent loading in developing oocytes, consistent with operating in different pathways. Abrogation of KU- or Theta-mediated end joining elicits opposite effects in brc-1; parg-1 doubles, highlighting differential involvement of DNA repair pathways and suggesting a profound impact in influencing DNA repair pathway choice by BRC-1-PARG-1. Importantly, lack of PARG-1 catalytic activity suppresses untimely accumulation of RAD-51 foci in brc-1 mutants but is only partially required to maintain fertility. Altogether, our data show that BRC-1/BRD-1-PARG-1 joined function is essential to keep genome integrity in meiotic cells by regulating multiple DNA repair pathways.