Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination

Abstract

Crossover recombination facilitates the accurate segregation of homologous chromosomes during meiosis1,2. In mammals, poorly characterized regulatory processes ensure that every pair of chromosomes obtains at least one crossover, even though most recombination sites yield non-crossovers3. Designation of crossovers involves selective localization of the SUMO ligase RNF212 to a minority of recombination sites, where it stabilizes pertinent factors such as MutSγ (ref. 4). Here we show that the ubiquitin ligase HEI10 (also called CCNB1IP1)5,6 is essential for this crossover/non-crossover differentiation process. In HEI10-deficient mice, RNF212 localizes to most recombination sites, and dissociation of both RNF212 and MutSγ from chromosomes is blocked. Consequently, recombination is impeded, and crossing over fails. In wild-type mice, HEI10 accumulates at designated crossover sites, suggesting that it also has a late role in implementing crossing over. As with RNF212, dosage sensitivity for HEI10 indicates that it is a limiting factor for crossing over. We suggest that SUMO and ubiquitin have antagonistic roles during meiotic recombination that are balanced to effect differential stabilization of recombination factors at crossover and non-crossover sites.

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Figure 1: RNF212 does not dissociate from synaptonemal complexes in Hei10 mei4/mei4 mutant spermatocytes.
Figure 2: Persistence of MutSγ complexes in Hei10mei4/mei4 spermatocytes.
Figure 3: Repair of DSBs is delayed in Hei10mei4/mei4 spermatocytes.
Figure 4: HEI10 localization to synaptonemal complexes and crossover sites.
Figure 5: Genetic requirements for HEI10 localization.
Figure 6: Dosage sensitivity of the HEI10 crossover function.

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Acknowledgements

We thank A. Kong for communicating unpublished results. This work was supported by US National Institutes of Health (NIH) grants R01GM084955 to N.H., R01GM45415 to J.S. and HD041012 to P.E.C. and by National Science Foundation grant CAREER 0844941 to J.W. N.H. is an investigator of the Howard Hughes Medical Institute.

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H.Q., H.B.D.P.R., Y.Y., J.W. and N.H. conceived and designed the experiments. H.Q., H.B.D.P.R., Y.Y., J.H.F., J.M.C., D.C.D., K.E.N., R.K.S., E.S., J.K.H., J.W. and N.H. performed the experiments. H.Q., H.B.D.P.R., Y.Y., J.H.F., J.W. and N.H. analyzed the data. J.S., E.S. and P.E.C. contributed reagents, materials and/or analysis tools. H.Q., H.B.D.P.R., Y.Y., J.W. and N.H. wrote the manuscript.

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Correspondence to Neil Hunter.

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The authors declare no competing financial interests.

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Qiao, H., Prasada Rao, H., Yang, Y. et al. Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination. Nat Genet 46, 194–199 (2014). https://doi.org/10.1038/ng.2858

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