Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France.
Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, Netherlands.
Sci Adv. 2023 Oct 27;9(43):eadi7352. doi: 10.1126/sciadv.adi7352.
In meiotic homologous recombination (HR), BRCA2 facilitates loading of the recombinases RAD51 and DMC1 at the sites of double-strand breaks (DSBs). The HSF2BP-BRME1 complex interacts with BRCA2. Its absence causes a severe reduction in recombinase loading at meiotic DSB. We previously showed that, in somatic cancer cells ectopically producing HSF2BP, DNA damage can trigger HSF2BP-dependent degradation of BRCA2, which prevents HR. Here, we report that, upon binding to BRCA2, HSF2BP forms octameric rings that are able to interlock into a large ring-shaped 24-mer. Addition of BRME1 leads to dissociation of both of these ring structures and cancels the disruptive effect of HSF2BP on cancer cell resistance to DNA damage. It also prevents BRCA2 degradation during interstrand DNA crosslink repair in egg extracts. We propose that, during meiosis, the control of HSF2BPBRCA2 oligomerization by BRME1 ensures timely assembly of the ring complex that concentrates BRCA2 and controls its turnover, thus promoting HR.
在减数分裂同源重组 (HR) 中，BRCA2 促进了重组酶 RAD51 和 DMC1 在双链断裂 (DSB) 位点的加载。HSF2BP-BRME1 复合物与 BRCA2 相互作用。其缺失导致减数分裂 DSB 处的重组酶加载严重减少。我们之前曾表明，在异位产生 HSF2BP 的体癌细胞中，DNA 损伤可触发 HSF2BP 依赖性 BRCA2 降解，从而阻止 HR。在这里，我们报告说，HSF2BP 与 BRCA2 结合后，形成八聚体环，能够交错成一个大的环形 24 聚体。添加 BRME1 会导致这两种环结构的解离，并取消 HSF2BP 对癌细胞抵抗 DNA 损伤的破坏作用。它还可以防止卵提取物中链间 DNA 交联修复过程中 BRCA2 的降解。我们提出，在减数分裂过程中，BRME1 对 HSF2BP-BRCA2 寡聚化的控制确保了环复合物的及时组装，该复合物浓缩 BRCA2 并控制其周转，从而促进 HR。
