BRCA1 and BRCA2 Tumor Suppressor Function in Meiosis.

Qianyan Li,Joanne Engebrecht

doi:10.3389/fcell.2021.668309

Abstract

Meiosis is a specialized cell cycle that results in the production of haploid gametes for sexual reproduction. During meiosis, homologous chromosomes are connected by chiasmata, the physical manifestation of crossovers. Crossovers are formed by the repair of intentionally induced double strand breaks by homologous recombination and facilitate chromosome alignment on the meiotic spindle and proper chromosome segregation. While it is well established that the tumor suppressors BRCA1 and BRCA2 function in DNA repair and homologous recombination in somatic cells, the functions of BRCA1 and BRCA2 in meiosis have received less attention. Recent studies in both mice and the nematode Caenorhabditis elegans have provided insight into the roles of these tumor suppressors in a number of meiotic processes, revealing both conserved and organism-specific functions. BRCA1 forms an E3 ubiquitin ligase as a heterodimer with BARD1 and appears to have regulatory roles in a number of key meiotic processes. BRCA2 is a very large protein that plays an intimate role in homologous recombination. As women with no indication of cancer but carrying BRCA mutations show decreased ovarian reserve and accumulated oocyte DNA damage, studies in these systems may provide insight into why BRCA mutations impact reproductive success in addition to their established roles in cancer.

Highlights

Homologous recombination (HR) is a high-fidelity pathway that mediates error-free repair of DNA double strand breaks (DSBs) and is essential for maintaining genome integrity
It is likely that C. elegans BRC-2 has acquired this function to promote single strand annealing (SSA) during meiosis, as an ortholog of RAD52, which mediates SSA, is missing. That organisms such as mice, C. elegans, and A. thaliana carrying mutations in their respective Breast cancer susceptibility gene 1 (BRCA1) and Breast cancer susceptibility gene 2 (BRCA2) orthologs exhibit meiotic phenotypes is consistent with BRCA1 and BRCA2 playing critical roles in meiosis
BRCA1 is essential for meiotic sex chromosome inactivation (MSCI) in mice but is dispensable for MSCI in C. elegans, while C. elegans BRC-1 promotes DNA end resection, stabilizes the RAD-51 filament and regulates the crossover landscape

Summary

Introduction

Homologous recombination (HR) is a high-fidelity pathway that mediates error-free repair of DNA double strand breaks (DSBs) and is essential for maintaining genome integrity. In addition to MSCI failure, spermatocytes from Brca1∆11/∆11 Trp53+/− mice exhibited a prolonged autosomal γH2AX signal with greatly reduced numbers of RAD51 (but not DMC1) and MLH1 foci, suggesting that BRCA1 plays a role in meiotic DSBs repair and crossover formation (Xu et al, 2003).

Results

Conclusion