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Topoisomerase II mediates meiotic crossover interference

Nature volume 511, pages 551556 (31 July 2014) | Download Citation

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Abstract

Spatial patterning is a ubiquitous feature of biological systems. Meiotic crossovers provide an interesting example, defined by the classic phenomenon of crossover interference. Here we identify a molecular pathway for interference by analysing crossover patterns in budding yeast. Topoisomerase II plays a central role, thus identifying a new function for this critical molecule. SUMOylation (of topoisomerase II and axis component Red1) and ubiquitin-mediated removal of SUMOylated proteins are also required. The findings support the hypothesis that crossover interference involves accumulation, relief and redistribution of mechanical stress along the protein/DNA meshwork of meiotic chromosome axes, with topoisomerase II required to adjust spatial relationships among DNA segments.

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References

  1. 1.

    , , & in Genome Organization and Function in the Cell Nucleus (ed. ) 487–533 (John Wiley, 2011)

  2. 2.

    & The leptotene-zygotene transition of meiosis. Annu. Rev. Genet. 32, 619–697 (1998)

  3. 3.

    & Meiotic crossing-over: obligation and interference. Cell 126, 246–248 (2006)

  4. 4.

    et al. A mechanical basis for chromosome function. Proc. Natl Acad. Sci. USA 101, 12592–12597 (2004)

  5. 5.

    The mechanism of crossing over, parts I–IV. Am. Nat. 50, 193–434 (1916)

  6. 6.

    The behavior of the chromosomes as studied through linkage. Z. indukt. Abstamm.-u. VererbLehre 13, 234–287 (1915)

  7. 7.

    & Chromosome-wide control of meiotic crossing over in C. elegans. Curr. Biol. 13, 1641–1647 (2003)

  8. 8.

    , , & Crossover patterning by the Beam-Film model: analysis and implications. PLoS Genet. 10, e1004042 (2014)

  9. 9.

    & A polymerization model of chiasma interference and corresponding computer simulation. Genetics 126, 1127–1138 (1990)

  10. 10.

    , & Cell-free study of F plasmid partition provides evidence for cargo transport by a diffusion-ratchet mechanism. Proc. Natl Acad. Sci. USA 110, E1390–E1397 (2013)

  11. 11.

    , , & Physical and functional interactions among basic chromosome organizational features govern early steps of meiotic chiasma formation. Cell 111, 791–802 (2002)

  12. 12.

    et al. A hierarchical combination of factors shapes the genome-wide topography of yeast meiotic recombination initiation. Cell 144, 719–731 (2011)

  13. 13.

    et al. Recombination proteins mediate meiotic spatial chromosome organization and pairing. Cell 141, 94–106 (2010)

  14. 14.

    , & Crossover/noncrossover differentiation, synaptonemal complex formation, and regulatory surveillance at the leptotene/zygotene transition of meiosis. Cell 117, 29–45 (2004)

  15. 15.

    in Molecular Genetics of Recombination, Topics in Current Genetics (eds and ) 381–442 (Springer, 2006)

  16. 16.

    & Synaptonemal complex formation: where does it start? Bioessays 27, 995–998 (2005)

  17. 17.

    & Early decision; meiotic crossover interference prior to stable strand exchange and synapsis. Cell 117, 9–15 (2004)

  18. 18.

    , , & Imposition of crossover interference through the nonrandom distribution of synapsis initiation complexes. Cell 116, 795–802 (2004)

  19. 19.

    & Zip3 provides a link between recombination enzymes and synaptonemal complex proteins. Cell 102, 245–255 (2000)

  20. 20.

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

  21. 21.

    et al. Gene conversion and crossing over along the 405-kb left arm of Saccharomyces cerevisiae chromosome VII. Genetics 168, 49–63 (2004)

  22. 22.

    , , , & The SUMO-1 isopeptidase Smt4 is linked to centromeric cohesion through SUMO-1 modification of DNA topoisomerase II. Mol. Cell 9, 1169–1182 (2002)

  23. 23.

    & Meiosis-specific arrest revealed in DNA topoisomerase II mutants. Mol. Cell. Biol. 13, 3445–3455 (1993)

  24. 24.

    , , & Crossover homeostasis in yeast meiosis. Cell 126, 285–295 (2006)

  25. 25.

    & Top2 SUMO conjugation in yeast cell lysates. Methods Mol. Biol. 582, 209–219 (2009)

  26. 26.

    & Synaptonemal complex formation and meiotic checkpoint signaling are linked to the lateral element protein Red1. Proc. Natl Acad. Sci. USA 107, 11370–11375 (2010)

  27. 27.

    & A Role for SUMO in meiotic chromosome synapsis. Curr. Biol. 16, 1238–1243 (2006)

  28. 28.

    , & Nuclear organization in genome stability: SUMO connections. Cell Res. 21, 474–485 (2011)

  29. 29.

    , , & Slx5 promotes transcriptional silencing and is required for robust growth in the absence of Sir2. Mol. Cell. Biol. 28, 1361–1372 (2008)

  30. 30.

    et al. Sex-specific crossover distributions and variations in interference level along Arabidopsis thaliana chromosome 4. PLoS Genet. 3, e106 (2007)

  31. 31.

    , , & Crossover interference underlies sex differences in recombination rates. Trends Genet. 23, 539–542 (2007)

  32. 32.

    et al. Genome analyses of single human oocytes. Cell 155, 1492–1506 (2013)

  33. 33.

    Chiasma formation: chromatin/axis interplay and the role(s) of the synaptonemal complex. Chromosoma 115, 175–194 (2006)

  34. 34.

    et al. Cohesin Smc1beta determines meiotic chromatin axis loop organization. J. Cell Biol. 180, 83–90 (2008)

  35. 35.

    et al. Localization of RAP1 and topoisomerase II in nuclei and meiotic chromosomes of yeast. J. Cell Biol. 117, 935–948 (1992)

  36. 36.

    & Anti-topoisomerase II recognizes meiotic chromosome cores. Chromosoma 98, 317–322 (1989)

  37. 37.

    , & Chromosome capture brings it all together. Science 342, 940–941 (2013)

  38. 38.

    et al. Conjugation of human topoisomerase 2α with small ubiquitin-like modifiers 2/3 in response to topoisomerase inhibitors: cell cycle stage and chromosome domain specificity. Cancer Res. 68, 2409–2418 (2008)

  39. 39.

    & SUMO modification of DNA topoisomerase II: trying to get a CENse of it all. DNA Repair 8, 557–568 (2009)

  40. 40.

    et al. Mitotic chromosomes are constrained by topoisomerase II-sensitive DNA entanglements. J. Cell Biol. 188, 653–663 (2010)

  41. 41.

    , & Proteolysis of mitotic chromosomes induces gradual and anisotropic decondensation correlated with a reduction of elastic modulus and structural sensitivity to rarely cutting restriction enzymes. Mol. Biol. Cell 17, 104–113 (2006)

  42. 42.

    , , & Meiotic chromosome structures constrain and respond to designation of crossover sites. Nature 502, 703–706 (2013)

  43. 43.

    in Centromeric Functions and Dynamics of DNA Topoisomerase II in S. cerevisiae 130–187. Ph.D. thesis, Univ. California Riverside. (2009)

  44. 44.

    et al. Global analysis of the meiotic crossover landscape. Dev. Cell 15, 401–415 (2008)

  45. 45.

    , , , & High-resolution mapping of meiotic crossovers and non-crossovers in yeast. Cell 454, 479–485 (2008)

  46. 46.

    et al. Genetic and physical maps of Saccharomyces cerevisiae. Nature 387, 67–73 (1997)

  47. 47.

    , , & Competing crossover pathways act during meiosis in Saccharomyces cerevisiae. Genetics 168, 1805–1816 (2004)

  48. 48.

    et al. The Mus81/Mms4 endonuclease acts independently of double-Holliday junction resolution to promote a distinct subset of crossovers during meiosis in budding yeast. Genetics 164, 81–94 (2003)

  49. 49.

    , & MSH5, a novel MutS homolog, facilitates meiotic reciprocal recombination between homologs in Saccharomyces cerevisiae but not mismatch repair. Genes Dev. 9, 1728–1739 (1995)

  50. 50.

    & Zip2, a meiosis-specific protein required for the initiation of chromosome synapsis. Cell 93, 349–359 (1998)

  51. 51.

    , , & Crossover assurance and crossover interference are distinctly regulated by the ZMM proteins during yeast meiosis. Nature Genet. 40, 299–309 (2008)

  52. 52.

    , , & Meiotic chromosome synapsis-promoting proteins antagonize the anti-crossover activity of Sgs1. PLoS Genet. 2, e155 (2006)

  53. 53.

    & Tying synaptonemal complex initiation to the formation and programmed repair of DNA double-strand breaks. Proc. Natl Acad. Sci. USA 101, 4519–4524 (2004)

  54. 54.

    & Crossover interference is abolished in the absence of a synaptonemal complex protein. Cell 79, 283–292 (1994)

  55. 55.

    et al. The baker’s yeast diploid genome is remarkably stable in vegetative growth and meiosis. PLoS Genet. 6, e1001109 (2010)

  56. 56.

    et al. Numerical constraints and feedback control of double-strand breaks in mouse meiosis. Genes Dev. 27, 873–886 (2013)

  57. 57.

    , , & Differential association of the conserved SUMO ligase Zip3 with meiotic double-strand break sites reveals regional variations in the outcome of meiotic recombination. PLoS Genet. 9, e1003416 (2013)

  58. 58.

    et al. Sister cohesion and structural axis components mediate homolog bias of meiotic recombination. Cell 143, 924–937 (2010)

  59. 59.

    & Dynamic chromosome movements during meiosis: a way to eliminate unwanted connections? Trends Cell Biol. 19, 716–724 (2009)

  60. 60.

    , & Genetic and morphological approaches for the analysis of meiotic chromosomes in yeast. Methods Cell Biol. 53, 257–285 (1998)

  61. 61.

    The spatial distribution of cross-overs in X-chromosome tetrads of Drosophila melanogaster. J. Genet. 36, 103–126 (1938)

  62. 62.

    , , & Meiotic double-strand breaks occur once per pair of (sister) chromatids and, via Mec1/ATR and Tel1/ATM, once per quartet of chromatids. Proc. Natl Acad. Sci. USA 108, 20036–20041 (2011)

  63. 63.

    , , & Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000)

  64. 64.

    , & Targeted sister chromatid cohesion by Sir2. PLoS Genet. 7, e1002000 (2011)

  65. 65.

    & A histone variant, Htz1p, and a Sir1p-like protein, Esc2p, mediate silencing at HMR. Mol. Cell 6, 769–780 (2000)

  66. 66.

    , & HST1, a new member of the SIR2 family of genes. Yeast 12, 631–640 (1996)

  67. 67.

    et al. The logic and mechanism of homologous recombination partner choice. Mol. Cell 51, 440–453 (2013)

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Acknowledgements

We thank M. Hochstrasser, J. Bachant, S. Jentsch, L. Pillus and M. Weinreich for plasmids, J. Fung for Zip2 focus data, D. Zickler for the image in Fig. 6a, and members of the Kleckner laboratory and D. Zickler for advice and discussions. This research, L.Z., S.W., S.Y. and N.K. were supported by a grant to N.K. from the National Institutes of Health (RO1 GM044794); S.H. and K.P.K. were supported by the National Research Foundation of Korea funded by the Ministry of Science, ICT and Future Planning (2012-M3A9C6050367).

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Affiliations

  1. Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Liangran Zhang
    • , Shunxin Wang
    • , Shen Yin
    •  & Nancy Kleckner
  2. Department of Life Science, Chung-Ang University, Seoul 156-756, South Korea

    • Soogil Hong
    •  & Keun P. Kim

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Contributions

L.Z. and N.K. conceived and designed experiments, analysed data and wrote the paper. L.Z., S.W., Y.S., S.H. and K.P.K. performed experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nancy Kleckner.

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https://doi.org/10.1038/nature13442

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