PARG and BRCA1-BARD1 cooperative function regulates DNA repair pathway choice during gametogenesis
| Authors | |
|---|---|
| Year of publication | 2022 |
| Type | Article in Periodical |
| Magazine / Source | Nucleic acids research |
| MU Faculty or unit | |
| Citation | |
| Web | https://academic.oup.com/nar/article/50/21/12291/6882108?login=true |
| Doi | http://dx.doi.org/10.1093/nar/gkac1153 |
| Keywords | PARG; BRCA1–BARD1; DNA repair pathway choice; gametogenesis |
| Description | Meiotic chromosome segregation relies on programmed DNA double-strand break induction. These are in turn repaired by homologous recombination, generating physical attachments between the parental chromosomes called crossovers. A subset of breaks yields recombinant outcomes, while crossover-independent mechanisms repair the majority of lesions. The balance between different repair pathways is crucial to ensure genome integrity. We show that Caenorhabditis elegans BRC-1/BRCA1-BRD-1/BARD1 and PARG-1/PARG form a complex in vivo, essential for accurate DNA repair in the germline. Simultaneous depletion of BRC-1 and PARG-1 causes synthetic lethality due to reduced crossover formation and impaired break repair, evidenced by hindered RPA-1 removal and presence of aberrant chromatin bodies in diakinesis nuclei, whose formation depends on spo-11 function. These factors undergo a similar yet 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, 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 for fertility. Our data show that BRC-1/BRD-1-PARG-1 joint function is essential for genome integrity in meiotic cells by regulating multiple DNA repair pathways. |
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