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bioRxiv · 10.1101/2025.08.25.672081

HEIP1 orchestrates pro-crossover protein activity during mammalian meiosis

De Muyt, A.·Lee, S.·Khanal, S.·Dal Toe, L.·Adam, C.·Mercier, R.·Borde, V.·Hunter, N.·ROBERT, T.
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Abstract

Meiotic crossovers are needed to produce genetically balanced gametes. In mammals, crossover formation is mediated by a conserved set of pro-crossover proteins via mechanisms that remain unclear. Here, we characterize a mammalian pro-crossover factor HEIP1. In mouse HEIP1 is essential for crossing over and fertility of both sexes. HEIP1 promotes crossing over by orchestrating the recruitment of other pro-crossover proteins, including the MutS{gamma} complex (MSH4- MSH5) and E3 ligases (HEI10, RNF212, and RNF212B), that are required to mature crossover sites and recruit the crossover-specific resolution complex MutL{gamma}. Moreover, HEIP1 directly interacts with HEI10, suggesting a direct role in controlling the recruitment of pro-crossover E3 ligases. During early stages of meiotic prophase I, HEIP1 interacts with the chromosome axes, independently of recombination, before relocalizing to the central region of the synaptonemal complex. We propose that HEIP1 is a new conserved master regulator of crossover proteins that controls different crossover maturation steps. Significance StatementCrossovers are essential to produce gametes by promoting the proper segregation of the homologous chromosomes. But, if misregulated, they can lead to genetic disorders, miscarriage and infertility. Their formation depends on the conserved pro-crossover factors, which repertoire is expanding and mode of action tightly regulated. This study highlights how the HEIP1 protein organizes pro-crossover protein activities in the mouse. Our findings show that HEIP1, by interacting early with chromosomes independently of recombination initiation, and orchestrating the recruitment of pro-crossover factors, including the MutSg complex and the RING proteins HEI10, RNF212 and RNF212B, is pivotal in this regulation. Our work is of significance to unravel crossover control during meiotic recombination, a conserved mechanism essential for gametes formation.

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De Muyt, A., Lee, S., Khanal, S., Dal Toe, L., Adam, C., Mercier, R., Borde, V., Hunter, N., ROBERT, T.. 2025-08-28. HEIP1 orchestrates pro-crossover protein activity during mammalian meiosis. https://doi.org/10.1101/2025.08.25.672081

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