The FIGNL1-FIRRM complex is required to complete meiotic recombination in the mouse and prevents massive DNA damage-independent RAD51 and DMC1 loading

During meiosis, nucleoprotein filaments of the strand exchange proteins RAD51 and DMC1 are crucial for repairing SPO11-generated DNA double-strand breaks (DSBs) by homologous recombination (HR). A balanced activity of positive and negative RAD51/DMC1 regulators ensures proper recombination. Fidgetin-like 1 (FIGNL1) was previously shown to negatively regulates RAD51 in human cells. However, FIGNL1’s role during meiotic recombination in mammals remains unknown. Here, we deciphered the meiotic functions of FIGNL1 and of FIGNL1 interacting regulator of recombination and mitosis (FIRRM) using male germline-specific conditional knock-out (cKO) mouse models. Both FIGNL1 and FIRRM are required for completing meiotic prophase in mouse spermatocytes. Despite efficient recruitment of DMC1 on ssDNA at meiotic DSB hotspots, the formation of late recombination intermediates is defective inFirrmcKO andFignl1cKO spermatocytes. Moreover, the FIGNL1-FIRRM complex limits RAD51 and DMC1 accumulation on intact chromatin, independently from the formation of SPO11- catalyzed DSBs. Purified human FIGNL1ΔN alters the RAD51/DMC1 nucleoprotein filament structure and inhibits strand invasionin vitro. Thus, this complex might regulate RAD51 and DMC1 association at sites of meiotic DSBs to promote proficient strand invasion and processing of recombination intermediates.

Keyword(s)

meiosis, homologous recombination, FIGNL1, FIRRM, RAD51, DMC1

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Zainu Akbar, Dupaigne Pauline, Bouchouika Soumya, Cau Julien, Clement Julie A. J., Auffret Pauline, Ropars Virginie, Charbonnier Jean-Baptiste, de Massy Bernard, Kumar Rajeev, Baudat Frédéric (2023). The FIGNL1-FIRRM complex is required to complete meiotic recombination in the mouse and prevents massive DNA damage-independent RAD51 and DMC1 loading. bioRxiv. INPRESS. https://doi.org/10.1101/2023.05.17.541096, https://archimer.ifremer.fr/doc/00847/95918/

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