Brca2 is a predisposition gene for breast and ovarian cancers. It encodes the BRCA2 protein involved in the repair of DNA double-strand breaks by homologous recombination, whether in somatic cells whose DNA has been accidentally damaged, or in germ cells whose DNA undergoes programmed breaks to increase genetic diversity.
During homologous recombination, BRCA2 facilitates the loading of recombinases at the sites of double-strand breaks. During meiosis, the HSF2BP-BRME1 complex interacts with BRCA2 and helps to regulate this loading. Loss of HSF2BP or BRME1 does not lead to embryonic lethality but causes complete failure of spermatogenesis due to a significant reduction in recombinase accumulation at meiotic DNA double-strand breaks, preventing DNA strand crossing and homologous recombination.
Paradoxically, a team from the Eramus Medical Center (Rotterdam, The Netherlands) has shown that in somatic cancer cells with overproduction of HSF2BP, certain DNA damage can trigger HSF2BP-dependent BRCA2 degradation and prevent homologous recombination.
The Dutch team identified a disordered region of BRCA2 that is necessary and sufficient to interact with the HSF2BP protein. To analyse the structure of the BRCA2-HFS2BP complex, the team collaborated with Sophie Zinn-Justin's team at the I2BC (CNRS/CEA/UPSaclay, Gif-sur-Yvette) and benefited from access to the structural biology platforms at the I2BC, the Institut Pasteur (Paris) and the Synchrotron Soleil (Gif-sur-Yvette).
The researchers used cryo-electron microscopy to model the three-dimensional structure of the complex formed by the disordered 51 amino acid fragment of BRCA2 and the whole HSF2BP protein (37 kDa).
The results are published in the journal Science Advances. The size and shape of this complex are unexpected. The interaction between the BRCA2 peptide and a tetramer of HSF2BP causes the assembly of an octameric ring and three of these rings can interlock to form an even larger ring structure (⌀ ~ 200 Å) composed of 12 fragments of BRCA2 and 24 HSF2BP (900 kDa). A 40 amino acid peptide from the BRME1 protein is able to dissociate this ring structure and negates the disruptive effect of HSF2BP on cancer cell resistance to DNA damage. BRME1 also prevents the degradation of BRCA2 during the repair of DNA inter-strand covalent bonds in extracts of xenopus eggs.
The researchers propose that, during meiosis, HSF2BP and BRME1 opportunistically regulate the concentration of BRCA2 and its degradation, in order to facilitate BRCA2-mediated repair of double-strand breaks.
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