Year: 2022
Type: article
Abstract: Meiosis requires the formation of programmed DNA double strand breaks (DSBs), essential for fertility and for generating genetic diversity. DSBs are induced by the catalytic activity of the TOPOVIL complex formed by SPO11 and TOPOVIBL. To ensure genomic integrity, DNA cleavage activity is tightly regulated, and several accessory factors (REC114, MEI4, IHO1, and MEI1) are needed for DSB formation in mice. How and when these proteins act is not understood. Here, we show that REC114 is a direct partner of TOPOVIBL, and identify their conserved interacting domains by structural analysis. We then analyse the role of this interaction by monitoring meiotic DSBs in female and male mice carrying point mutations in TOPOVIBL that decrease or disrupt its binding to REC114. In these mutants, DSB activity is strongly reduced genome-wide in oocytes, and only in sub-telomeric regions in spermatocytes. In addition, in mutant spermatocytes, DSB activity is delayed in autosomes. These results suggest that REC114 is a key member of the TOPOVIL catalytic complex, and that the REC114/TOPOVIBL interaction ensures the efficiency and timing of DSB activity.
Source: Nature Communications
Institutions: Centre National de la Recherche Scientifique, Institut de Génétique Humaine, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut de Biologie Structurale, Université Grenoble Alpes, Inserm, Université de Montpellier, Centre de Biologie Structurale, Université Toulouse III - Paul Sabatier, Université de Toulouse, Centre de Biologie Intégrative de Toulouse
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,890
Funders: European Molecular Biology Laboratory, European Commission, Agence Nationale de la Recherche, European Synchrotron Radiation Facility, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Campus France, French Infrastructure for Integrated Structural Biology
Awards: G1064512522, G1183670895, CBH-EUR-GS, G256544642, G2659019386, G3207356259, G3789527517, G393177772, G434337789, G4399195447, G4656594441, PRES Towards International Gain of Excellence, G521208723, G5340643184, G5702163051, Reconstitution of the meiotic DNA double strand break complex and activity in vitro, G678225801, G6803667113, G6853435384, G7240651115, G7673705747, G7841029393, G814059, G8548513469, Infrastructure Française pour la Biologie Structurale Intégrée
OpenAlex ID: W4309235947