Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Uni Paris-Sud, Uni Paris-Saclay, Gif-sur-Yvette, France.
Department of Developmental Biology, Oncode Institute, Erasmus University Medical Center, 3000 CA, Rotterdam, The Netherlands.
Nat Commun. 2021 Jul 29;12(1):4605. doi: 10.1038/s41467-021-24871-6.
BRCA2 and its interactors are required for meiotic homologous recombination (HR) and fertility. Loss of HSF2BP, a BRCA2 interactor, disrupts HR during spermatogenesis. We test the model postulating that HSF2BP localizes BRCA2 to meiotic HR sites, by solving the crystal structure of the BRCA2 fragment in complex with dimeric armadillo domain (ARM) of HSF2BP and disrupting this interaction in a mouse model. This reveals a repeated 23 amino acid motif in BRCA2, each binding the same conserved surface of one ARM domain. In the complex, two BRCA2 fragments hold together two ARM dimers, through a large interface responsible for the nanomolar affinity - the strongest interaction involving BRCA2 measured so far. Deleting exon 12, encoding the first repeat, from mBrca2 disrupts BRCA2 binding to HSF2BP, but does not phenocopy HSF2BP loss. Thus, results herein suggest that the high-affinity oligomerization-inducing BRCA2-HSF2BP interaction is not required for RAD51 and DMC1 recombinase localization in meiotic HR.
BRCA2 及其相互作用因子对于减数分裂同源重组（HR）和生育能力是必需的。BRCA2 相互作用因子 HSF2BP 的缺失会破坏精子发生过程中的 HR。我们通过解决 BRCA2 片段与二聚体臂板域（ARM）的 HSF2BP 复合物的晶体结构，并在小鼠模型中破坏这种相互作用，来验证 HSF2BP 将 BRCA2 定位到减数分裂 HR 位点的模型。这揭示了 BRCA2 中存在一个重复的 23 个氨基酸基序，每个基序都与一个 ARM 结构域的相同保守表面结合。在复合物中，两个 BRCA2 片段通过一个负责纳摩尔亲和力的大界面将两个 ARM 二聚体保持在一起，这是迄今为止涉及 BRCA2 的最强相互作用。从 mBrca2 中删除编码第一个重复的外显子 12 会破坏 BRCA2 与 HSF2BP 的结合，但不会模拟 HSF2BP 的缺失表型。因此，本文的结果表明，高亲和力的寡聚诱导 BRCA2-HSF2BP 相互作用对于 RAD51 和 DMC1 重组酶在减数分裂 HR 中的定位不是必需的。
