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Article | Scientific result | Structural biology
By solving the three-dimensional structure of a fragment of the BRCA2-HSF2BP complex, a collaboration involving teams from I2BC and ERASMUS MC identifies the precise BRCA2 motif that causes the very high affinity between the two partners and shows that, in vivo, this complex has no function in the recruitment of Rad51 to meiotic sites of homologous recombination.
Brca2 is a well-established breast and ovarian cancer susceptibility gene. It codes for a protein (BRCA2) essential for homologous recombination (HR), a process central to DNA repair and meiosis. In particular, BRCA2 recruits the Rad51 protein to DNA in order to search for sequence homologies between two strands and allow their exchange. In addition to Rad51, BRCA2 interacts with other proteins. A team from the ERASMUS Medical Center (Rotterdam, The Netherlands) has recently identified one of its partners, HSF2BP. This protein is widely expressed in meiotic and cancer cells. Mutations in HSF2BP are implicated in fertility problems: in particular, loss of HSF2BP prevents homologous recombination during spermatogenesis.
In order to determine whether HSF2BP is involved in the localization of BRCA2 at homologous recombination sites during meiosis, the Nuclear Envelope, Telomeres and DNA Repair team of I2BC, in collaboration with teams from ERASMUS MC, the University of Salamanca (Spain) and the Synchrotron SOLEIL (Gif-sur-Yvette), solved the 3D structure of the interacting domains of BRCA2 and HSF2BP by X-ray crystallography. They identified a repeated motif in BRCA2 capable of binding two HSF2BP domains and showed that two BRCA2 fragments bind simultaneously to four HSF2BP domains, leading to a very high affinity between the two partners and to the formation of a tetramer of HSF2BP domains. Deletion of the first repeat of the motif found in BRCA2 strongly decreases the affinity between BRCA2 and HFS2BP and prevents tetramerization of the HSF2BP domain. However, this deletion does not reproduce the HFS2BP loss phenotype in vivo (in a mice model). The authors concluded that the high affinity interaction between BRCA2 and HFS2BP is not necessary for the recruitment of Rad51 to meiotic sites of homologous recombination. The full results were published in Nature Communications.
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Rania Ghouil, Simona Miron, Lieke Koornneef, Jasper Veerman, Maarten W Paul, Marie-Hélène Le Du, Esther Sleddens-Linkels, Sari E van Rossum-Fikkert, Yvette van Loon, Natalia Felipe-Medina, Alberto M Pendas, Alex Maas, Jeroen Essers, Pierre Legrand, Willy M Baarends, Roland Kanaar, Sophie Zinn-Justin, Alex N Zelensky. BRCA2 binding through a cryptic repeated motif to HSF2BP oligomers does not impact meiotic recombination. | Nature Communications 2021, Jul 29;12(1):4605
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.