Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

ATM controls meiotic double-strand-break formation

Nature volume 479, pages 237–240 (2011)Cite this article

Subjects

Abstract

In many organisms, developmentally programmed double-strand breaks (DSBs) formed by the SPO11 transesterase initiate meiotic recombination, which promotes pairing and segregation of homologous chromosomes1. Because every chromosome must receive a minimum number of DSBs, attention has focused on factors that support DSB formation2. However, improperly repaired DSBs can cause meiotic arrest or mutation3,4; thus, having too many DSBs is probably as deleterious as having too few. Only a small fraction of SPO11 protein ever makes a DSB in yeast or mouse5 and SPO11 and its accessory factors remain abundant long after most DSB formation ceases1, implying the existence of mechanisms that restrain SPO11 activity to limit DSB numbers. Here we report that the number of meiotic DSBs in mouse is controlled by ATM, a kinase activated by DNA damage to trigger checkpoint signalling and promote DSB repair. Levels of SPO11–oligonucleotide complexes, by-products of meiotic DSB formation, are elevated at least tenfold in spermatocytes lacking ATM. Moreover, Atm mutation renders SPO11–oligonucleotide levels sensitive to genetic manipulations that modulate SPO11 protein levels. We propose that ATM restrains SPO11 via a negative feedback loop in which kinase activation by DSBs suppresses further DSB formation. Our findings explain previously puzzling phenotypes of Atm-null mice and provide a molecular basis for the gonadal dysgenesis observed in ataxia telangiectasia, the human syndrome caused by ATM deficiency.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: SPO11 activity and expression in the absence of ATM.
Figure 2: SPO11–oligonucleotide complexes from juvenile mice.
Figure 3: Spo11 gene dosage modulates SPO11–oligonucleotide complex levels in Atm- deficient spermatocytes.
Figure 4: Roles of ATM in DSB formation and processing.

References

  1. Keeney, S. in Recombination and Meiosis: Crossing-Over and Disjunction Vol. 2 (ed. Lankenau, D. H. ) 81–123 (Springer, 2007)

    Google Scholar 

  2. Cole, F., Keeney, S. & Jasin, M. Evolutionary conservation of meiotic DSB proteins: more than just Spo11. Genes Dev. 24, 1201–1207 (2010)

    Article  CAS  Google Scholar 

  3. Sasaki, M., Lange, J. & Keeney, S. Genome destabilization by homologous recombination in the germ line. Nature Rev. Mol. Cell Biol. 11, 182–195 (2010)

    Article  CAS  Google Scholar 

  4. Hochwagen, A. & Amon, A. Checking your breaks: surveillance mechanisms of meiotic recombination. Curr. Biol. 16, R217–R228 (2006)

    Article  CAS  Google Scholar 

  5. Neale, M. J., Pan, J. & Keeney, S. Endonucleolytic processing of covalent protein-linked DNA double-strand breaks. Nature 436, 1053–1057 (2005)

    Article  CAS  ADS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Daniel, K. et al. Meiotic homologue alignment and its quality surveillance are controlled by mouse HORMAD1. Nature Cell Biol. 13, 599–610 (2011)

    Article  CAS  Google Scholar 

  8. Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996)

    Article  CAS  Google Scholar 

  9. Xu, Y. et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411–2422 (1996)

    Article  CAS  Google Scholar 

  10. Barlow, C. et al. Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. Development 125, 4007–4017 (1998)

    CAS  PubMed  Google Scholar 

  11. Di Giacomo, M. et al. Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. Proc. Natl Acad. Sci. USA 102, 737–742 (2005)

    Article  CAS  ADS  Google Scholar 

  12. Barchi, M. et al. Surveillance of different recombination defects in mouse spermatocytes yields distinct responses despite elimination at an identical developmental stage. Mol. Cell. Biol. 25, 7203–7215 (2005)

    Article  CAS  Google Scholar 

  13. Bellani, M. A., Romanienko, P. J., Cairatti, D. A. & Camerini-Otero, R. D. SPO11 is required for sex-body formation, and Spo11 heterozygosity rescues the prophase arrest of Atm−/− spermatocytes. J. Cell Sci. 118, 3233–3245 (2005)

    Article  CAS  Google Scholar 

  14. Barchi, M. et al. ATM promotes the obligate XY crossover and both crossover control and chromosome axis integrity on autosomes. PLoS Genet. 4, e1000076 (2008)

    Article  Google Scholar 

  15. Keeney, S. et al. A mouse homolog of the Saccharomyces cerevisiae meiotic recombination DNA transesterase Spo11p. Genomics 61, 170–182 (1999)

    Article  CAS  Google Scholar 

  16. Shannon, M., Richardson, L., Christian, A., Handel, M. A. & Thelen, M. P. Differential gene expression of mammalian SPO11/TOP6A homologs during meiosis. FEBS Lett. 462, 329–334 (1999)

    Article  CAS  Google Scholar 

  17. Bellani, M. A., Boateng, K. A., McLeod, D. & Camerini-Otero, R. D. The expression profile of the major mouse SPO11 isoforms indicates that SPO11β introduces double strand breaks and suggests that SPO11α has an additional role in prophase in both spermatocytes and oocytes. Mol. Cell. Biol. 30, 4391–4403 (2010)

    Article  CAS  Google Scholar 

  18. Kauppi, L. et al. Distinct properties of the XY pseudoautosomal region crucial for male meiosis. Science 331, 916–920 (2011)

    Article  CAS  ADS  Google Scholar 

  19. Romanienko, P. J. & Camerini-Otero, R. D. Cloning, characterization, and localization of mouse and human SPO11. Genomics 61, 156–169 (1999)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Bellve, A. R. et al. Spermatogenic cells of the prepuberal mouse. Isolation and morphological characterization. J. Cell Biol. 74, 68–85 (1977)

    Article  CAS  Google Scholar 

  22. 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)

    Article  CAS  Google Scholar 

  23. Terasawa, M., Ogawa, T., Tsukamoto, Y. & Ogawa, H. Sae2p phosphorylation is crucial for cooperation with Mre11p for resection of DNA double-strand break ends during meiotic recombination in Saccharomyces cerevisiae. Genes Genet. Syst. 83, 209–217 (2008)

    Article  CAS  Google Scholar 

  24. Sasanuma, H. et al. Cdc7-dependent phosphorylation of Mer2 facilitates initiation of yeast meiotic recombination. Genes Dev. 22, 398–410 (2008)

    Article  CAS  Google Scholar 

  25. Mahadevaiah, S. K. et al. Recombinational DNA double-strand breaks in mice precede synapsis. Nature Genet. 27, 271–276 (2001)

    Article  CAS  Google Scholar 

  26. Sedgwick, R. P. & Boder, E. in Handbook of Clinical Neurology Vol. 16 (ed. de Jong, J. M. B. V. ) 347–423 (Elsevier, 1991)

    Google Scholar 

  27. Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749–1753 (1995)

    Article  CAS  ADS  Google Scholar 

  28. Edelmann, W. et al. Meiotic pachytene arrest in MLH1-deficient mice. Cell 85, 1125–1134 (1996)

    Article  CAS  Google Scholar 

  29. Pittman, D. L. et al. Meiotic prophase arrest with failure of chromosome synapsis in mice deficient for Dmc1, a germline-specific RecA homolog. Mol. Cell 1, 697–705 (1998)

    Article  CAS  Google Scholar 

  30. 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)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Neale for discussions, R. Cha and K. McKim for sharing data before publication, and M. Hwang for assistance in monoclonal antibody development. This work was supported by NIH grants HD040916 and HD053855 (to M.J. and S.K.) and GM058673 (to S.K.). J.P. was supported in part by a Leukemia and Lymphoma Society Fellowship and F.C. by a Ruth L. Kirschstein NRSA (F32 HD51392). S.K. is an Investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Jing Pan

    Present address: Present address: Cell Biology Department, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.,

Authors and Affiliations

  1. Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10065, New York, USA

    Julian Lange, Jing Pan & Scott Keeney

  2. Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10065, New York, USA

    Francesca Cole & Maria Jasin

  3. Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, 94550, California, USA

    Michael P. Thelen

  4. Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10065, New York, USA

    Scott Keeney

Authors
  1. Julian Lange
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesca Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael P. Thelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Jasin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Scott Keeney
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.L., J.P. and F.C. performed experiments. M.P.T. generated the anti-SPO11 monoclonal hybridoma line. J.L., M.J., and S.K. wrote the paper.

Corresponding authors

Correspondence to Maria Jasin or Scott Keeney.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figure

The file contains Supplementary Figure 1 with a legend. (PDF 401 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lange, J., Pan, J., Cole, F. et al. ATM controls meiotic double-strand-break formation. Nature 479, 237–240 (2011). https://doi.org/10.1038/nature10508

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10508

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing