By characterizing the interaction between fragments of BRCA2 and HSF2BP by NMR, SAXS and in vitro crystallography, as well as by immunoprecipitation in cells, teams from I2BC and ERASMUS MC identify the precise motif of BRCA2 at the origin of the very strong affinity between the two partners and shows that, in vivo, this complex has no function in the recruitment of Rad51 to the meiotic sites of homologous recombination.

The BRCA2 gene is known to the general public as a predisposition gene for breast and ovarian cancer. It codes for a protein (BRCA2) whose role in “homologous recombination” (RH), necessary for DNA repair and meiosis, is widely documented. BRCA2 serves in particular to recruit the Rad51 protein on the DNA to search for sequence homologies between two strands and to allow their exchange. In addition to Rad51, BRCA2 interacts with other proteins. A team of ERASMUS Medical Center (Rotterdam, The Netherlands) recently identified one of its partners, HSF2BP. This protein is widely expressed in meiotic cells and in cancer cells. Mutations in HSF2BP are implicated in fertility problems: in particular, the loss of HSF2BP prevents homologous recombination during spermatogenesis.

To find out if HSF2BP is involved in the localization of BRCA2 to homologous recombination sites during meiosis, the team Nuclear envelope, telomeres and DNA repair of the I2BC in collaboration with teams from ERASMUS MC, the University of Salamanca (Spain) and the SUN Synchrotron (Gif-sur-Yvette), identified by NMR the site of interaction between BRCA2 and HSF2BP, and resolved by X-ray crystallography the structure of the complex between these two proteins. She thus identified a repeated motif in BRCA2 capable of binding two domains of HSF2BP and showed that two fragments of BRCA2 bind simultaneously to four domains of HSF2BP, leading to a very strong affinity between the two partners and to the formation of a tetramer of HSF2BP domains. The deletion of the first repeat of the motif discovered in BRCA2 strongly decreases the affinity between BRCA2 and HFS2BP and prevents the tetramerization of the domain of HSF2BP studied. On the other hand, this deletion does not reproduce in vivo (in a rodent model) the loss phenotype of HFS2BP. The authors conclude that the high affinity interaction between BRCA2 and HFS2BP is not involved in the recruitment of Rad51 to meiotic sites of homologous recombination. All the results have been published in Nature Communications.

2021 12 An oligomeric complex formed during meiosis studied by structural biology 9d42c