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


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.


  1. 1

    Sakuno, T., Tanaka, K., Hauf, S. & Watanabe, Y. Repositioning of aurora B promoted by chiasmata ensures sister chromatid mono-orientation in meiosis I. Dev. Cell 21, 534–545 (2011).

    CAS  Article  Google Scholar 

  2. 2

    Hirose, Y. et al. Chiasmata promote monopolar attachment of sister chromatids and their co-segregation toward the proper pole during meiosis I. PLoS Genet. 7, e1001329 (2011).

    CAS  Article  Google Scholar 

  3. 3

    Jones, G.H. The control of chiasma distribution. Symp. Soc. Exp. Biol. 38, 293–320 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Reynolds, A. et al. RNF212 is a dosage-sensitive regulator of crossing-over during mammalian meiosis. Nat. Genet. 45, 269–278 (2013).

    CAS  Article  Google Scholar 

  5. 5

    Toby, G.G., Gherraby, W., Coleman, T.R. & Golemis, E.A. A novel RING finger protein, human enhancer of invasion 10, alters mitotic progression through regulation of cyclin B levels. Mol. Cell Biol. 23, 2109–2122 (2003).

    CAS  Article  Google Scholar 

  6. 6

    Ward, J.O. et al. Mutation in mouse hei10, an e3 ubiquitin ligase, disrupts meiotic crossing over. PLoS Genet. 3, e139 (2007).

    Article  Google Scholar 

  7. 7

    Kong, A. et al. Sequence variants in the RNF212 gene associate with genome-wide recombination rate. Science 319, 1398–1401 (2008).

    CAS  Article  Google Scholar 

  8. 8

    Fledel-Alon, A. et al. Variation in human recombination rates and its genetic determinants. PLoS ONE 6, e20321 (2011).

    CAS  Article  Google Scholar 

  9. 9

    Chowdhury, R., Bois, P.R., Feingold, E., Sherman, S.L. & Cheung, V.G. Genetic analysis of variation in human meiotic recombination. PLoS Genet. 5, e1000648 (2009).

    Article  Google Scholar 

  10. 10

    Kong, A. et al. Common and low-frequency variants associated with genome-wide recombination rate. Nat. Genet. 46, 11–16 (2014).

    CAS  Article  Google Scholar 

  11. 11

    Cheng, C.H. et al. SUMO modifications control assembly of synaptonemal complex and polycomplex in meiosis of Saccharomyces cerevisiae. Genes Dev. 20, 2067–2081 (2006).

    CAS  Article  Google Scholar 

  12. 12

    Strong, E.R. & Schimenti, J.C. Evidence implicating CCNB1IP1, a RING domain–containing protein required for meiotic crossing over in mice, as an E3 SUMO ligase. Genes (Basel) 1, 440–451 (2010).

    CAS  Article  Google Scholar 

  13. 13

    Kolas, N.K. & Cohen, P.E. Novel and diverse functions of the DNA mismatch repair family in mammalian meiosis and recombination. Cytogenet. Genome Res. 107, 216–231 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Snowden, T., Acharya, S., Butz, C., Berardini, M. & Fishel, R. hMSH4-hMSH5 recognizes Holliday junctions and forms a meiosis-specific sliding clamp that embraces homologous chromosomes. Mol. Cell 15, 437–451 (2004).

    CAS  Article  Google Scholar 

  15. 15

    Hunter, N. in Molecular Genetics of Recombination (eds. Aguilera, A. & Rothstein, R.) 381–442 (Springer-Verlag, Heidelberg, 2006).

  16. 16

    Carlton, P.M. Three-dimensional structured illumination microscopy and its application to chromosome structure. Chromosome Res. 16, 351–365 (2008).

    CAS  Article  Google Scholar 

  17. 17

    Chicheportiche, A., Bernardino-Sgherri, J., de Massy, B. & Dutrillaux, B. Characterization of Spo11-dependent and independent phospho-H2AX foci during meiotic prophase I in the male mouse. J. Cell Sci. 120, 1733–1742 (2007).

    CAS  Article  Google Scholar 

  18. 18

    Fernandez-Capetillo, O. et al. H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev. Cell 4, 497–508 (2003).

    CAS  Article  Google Scholar 

  19. 19

    Baudat, F., Manova, K., Yuen, J.P., Jasin, M. & Keeney, S. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol. Cell 6, 989–998 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Romanienko, P.J. & Camerini-Otero, R.D. The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol. Cell 6, 975–987 (2000).

    CAS  Article  Google Scholar 

  21. 21

    de Vries, F.A. et al. Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formation. Genes Dev. 19, 1376–1389 (2005).

    CAS  Article  Google Scholar 

  22. 22

    Lipkin, S.M. et al. Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat. Genet. 31, 385–390 (2002).

    CAS  Article  Google Scholar 

  23. 23

    Eaker, S., Cobb, J., Pyle, A. & Handel, M.A. Meiotic prophase abnormalities and metaphase cell death in MLH1-deficient mouse spermatocytes: insights into regulation of spermatogenic progress. Dev. Biol. 249, 85–95 (2002).

    CAS  Article  Google Scholar 

  24. 24

    Holloway, J.K., Booth, J., Edelmann, W., McGowan, C.H. & Cohen, P.E. MUS81 generates a subset of MLH1-MLH3–independent crossovers in mammalian meiosis. PLoS Genet. 4, e1000186 (2008).

    Article  Google Scholar 

  25. 25

    Qiao, H., Lohmiller, L. & Anderson, L. Cohesin proteins load sequentially during prophase I in tomato primary microsporocytes. Chromosome Res. 19, 193–207 (2011).

    CAS  Article  Google Scholar 

  26. 26

    Costa, Y. et al. Two novel proteins recruited by synaptonemal complex protein 1 (SYCP1) are at the centre of meiosis. J. Cell Sci. 118, 2755–2762 (2005).

    CAS  Article  Google Scholar 

  27. 27

    Cobb, J., Cargile, B. & Handel, M.A. Acquisition of competence to condense metaphase I chromosomes during spermatogenesis. Dev. Biol. 205, 49–64 (1999).

    CAS  Article  Google Scholar 

  28. 28

    Holloway, J.K., Morelli, M.A., Borst, P.L. & Cohen, P.E. Mammalian BLM helicase is critical for integrating multiple pathways of meiotic recombination. J. Cell Biol. 188, 779–789 (2010).

    CAS  Article  Google Scholar 

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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).

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