减数分裂特异性 C19orf57/4930432K21Rik/BRME1 调节 RAD51 和 DMC1 在小鼠减数分裂重组中双链断裂的定位。

Meiosis-Specific C19orf57/4930432K21Rik/BRME1 Modulates Localization of RAD51 and DMC1 to DSBs in Mouse Meiotic Recombination.

机构信息

Department of Chromosome Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto 860-0811, Japan; Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan.

Liaison Laboratory Research Promotion Center, IMEG, Kumamoto University, Kumamoto 860-0811, Japan.

出版信息

Cell Rep. 2020 May 26;31(8):107686. doi: 10.1016/j.celrep.2020.107686.

DOI:10.1016/j.celrep.2020.107686

PMID:32460033

Abstract

Meiotic recombination is critical for genetic exchange and generation of chiasmata that ensures faithful chromosome segregation during meiosis I. Meiotic recombination is initiated by DNA double-strand break (DSB) followed by multiple processes of DNA repair. The exact mechanisms for how recombinases localize to DSB remain elusive. Here, we show that C19orf57/4930432K21Rik/BRME1 is a player for meiotic recombination in mice. C19orf57/4930432K21Rik/BRME1 associates with single-stranded DNA (ssDNA) binding proteins, BRCA2 and MEILB2/HSF2BP, which are critical recruiters of recombinases onto DSB sites. Disruption of C19orf57/4930432K21Rik/BRME1 shows severe impact on DSB repair and male fertility. Remarkably, removal of ssDNA binding proteins from DSB sites is delayed, and reciprocally, the loading of RAD51 and DMC1 onto resected ssDNA is impaired in Brme1 knockout (KO) spermatocytes. We propose that C19orf57/4930432K21Rik/BRME1 modulates localization of recombinases to meiotic DSB sites through the interaction with the BRCA2-MEILB2/HSF2BP complex during meiotic recombination.

摘要

减数分裂重组对于遗传交换和交叉的产生至关重要，这确保了减数分裂 I 期间染色体的正确分离。减数分裂重组由 DNA 双链断裂（DSB）引发，随后是多种 DNA 修复过程。重组酶如何定位到 DSB 的确切机制仍不清楚。在这里，我们表明 C19orf57/4930432K21Rik/BRME1 是小鼠减数分裂重组的参与者。C19orf57/4930432K21Rik/BRME1 与单链 DNA（ssDNA）结合蛋白 BRCA2 和 MEILB2/HSF2BP 相关联，后者是将重组酶招募到 DSB 位点的关键蛋白。C19orf57/4930432K21Rik/BRME1 的缺失对 DSB 修复和雄性生育能力有严重影响。值得注意的是，BRME1 缺失的精母细胞中，ssDNA 结合蛋白从 DSB 位点的去除延迟，相反，RAD51 和 DMC1 加载到切除的 ssDNA 上受损。我们提出，C19orf57/4930432K21Rik/BRME1 通过与 BRCA2-MEILB2/HSF2BP 复合物相互作用，调节重组酶在减数分裂 DSB 位点的定位，从而调节减数分裂重组过程中的重组酶定位。