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.

A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging

Abstract

Although DNA damage is considered a driving force for aging, the nature of the damage that arises endogenously remains unclear. Replicative stress, a source of endogenous DNA damage, is prevented primarily by the ATR kinase. We have developed a mouse model of Seckel syndrome characterized by a severe deficiency in ATR. Seckel mice show high levels of replicative stress during embryogenesis, when proliferation is widespread, but this is reduced to marginal amounts in postnatal life. In spite of this decrease, adult Seckel mice show accelerated aging, which is further aggravated in the absence of p53. Together, these results support a model whereby replicative stress, particularly in utero, contributes to the onset of aging in postnatal life, and this is balanced by the replicative stress–limiting role of the checkpoint proteins ATR and p53.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Generation of a humanized allele of Seckel syndrome.
Figure 2: ATRS/S mice recapitulate human Seckel syndrome.
Figure 3: Premature aging of ATRS/S mice.
Figure 4: Accumulation of replicative stress in ATRS/S MEFs.
Figure 5: Response of ATRS/S MEFs to PIKK inhibitors.
Figure 6: Accumulation of replicative stress on ATRS/S embryos.
Figure 7: Replicative stress–driven apoptosis in proliferating areas of the developing brain.
Figure 8: Effect of p53 depletion on ATRS/S cells and mice.

Similar content being viewed by others

References

  1. Lombard, D.B. et al. DNA repair, genome stability, and aging. Cell 120, 497–512 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Sedelnikova, O.A. et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat. Cell Biol. 6, 168–170 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Rossi, D.J. et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Schumacher, B., Garinis, G.A. & Hoeijmakers, J.H. Age to survive: DNA damage and aging. Trends Genet. 24, 77–85 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Harper, J.W. & Elledge, S.J. The DNA damage response: ten years after. Mol. Cell 28, 739–745 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Xu, Y. & Baltimore, D. Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev. 10, 2401–2410 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Elson, A. et al. Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc. Natl. Acad. Sci. USA 93, 13084–13089 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Brown, E.J. & Baltimore, D. Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev. 17, 615–628 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. de Klein, A. et al. Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Curr. Biol. 10, 479–482 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. O'Driscoll, M., Ruiz-Perez, V.L., Woods, C.G., Jeggo, P.A. & Goodship, J.A. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat. Genet. 33, 497–501 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Seckel, H. Bird-Headed Dwarfs: Studies in Developmental Anthropology Including Human Proportions (Karger, Basel, Switzerland, 1960).

  13. Shanske, A., Caride, D.G., Menasse-Palmer, L., Bogdanow, A. & Marion, R.W. Central nervous system anomalies in Seckel syndrome: report of a new family and review of the literature. Am. J. Med. Genet. 70, 155–158 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Ruzankina, Y. et al. Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell 1, 113–126 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Butler, M.G., Hall, B.D., Maclean, R.N. & Lozzio, C.B. Do some patients with Seckel syndrome have hematological problems and/or chromosome breakage? Am. J. Med. Genet. 27, 645–649 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rossi, D.J., Jamieson, C.H. & Weissman, I.L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Rosen, C.J. & Bouxsein, M.L. Mechanisms of disease: is osteoporosis the obesity of bone? Nat. Clin. Pract. Rheumatol. 2, 35–43 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Morrison, S.J., Wandycz, A.M., Akashi, K., Globerson, A. & Weissman, I.L. The aging of hematopoietic stem cells. Nat. Med. 2, 1011–1016 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Sudo, K., Ema, H., Morita, Y. & Nakauchi, H. Age-associated characteristics of murine hematopoietic stem cells. J. Exp. Med. 192, 1273–1280 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bartke, A. Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146, 3718–3723 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Lombardi, G., Di Somma, C., Rota, F. & Colao, A. Associated hormonal decline in aging: is there a role for GH therapy in aging men? J. Endocrinol. Invest. 28, 99–108 (2005).

    CAS  PubMed  Google Scholar 

  22. van der Pluijm, I. et al. Impaired genome maintenance suppresses the growth hormone–insulin-like growth factor 1 axis in mice with Cockayne syndrome. PLoS Biol. 5, e2 (2007).

    Article  PubMed  Google Scholar 

  23. Niedernhofer, L.J. et al. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444, 1038–1043 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Cha, R.S. & Kleckner, N. ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones. Science 297, 602–606 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Sogo, J.M., Lopes, M. & Foiani, M. Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects. Science 297, 599–602 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Stiff, T. et al. Nbs1 is required for ATR-dependent phosphorylation events. EMBO J. 24, 199–208 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Casper, A.M., Nghiem, P., Arlt, M.F. & Glover, T.W. ATR regulates fragile site stability. Cell 111, 779–789 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Casper, A.M., Durkin, S.G., Arlt, M.F. & Glover, T.W. Chromosomal instability at common fragile sites in Seckel syndrome. Am. J. Hum. Genet. 75, 654–660 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bobabilla-Morales, L. et al. Chromosome instability induced in vitro with mitomycin C in five Seckel syndrome patients. Am. J. Med. Genet. A. 123A, 148–152 (2003).

    Article  PubMed  Google Scholar 

  30. Syrrou, M., Georgiou, I., Paschopoulos, M. & Lolis, D. Seckel syndrome in a family with three affected children and hematological manifestations associated with chromosome instability. Genet. Couns. 6, 37–41 (1995).

    CAS  PubMed  Google Scholar 

  31. Arnold, S.R., Spicer, D., Kouseff, B., Lacson, A. & Gilbert-Barness, E. Seckel-like syndrome in three siblings. Pediatr. Dev. Pathol. 2, 180–187 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Boscherini, B. et al. Intrauterine growth retardation. A report of two cases with bird-headed appearance, skeletal changes and peripheral GH resistance. Eur. J. Pediatr. 137, 237–242 (1981).

    Article  CAS  PubMed  Google Scholar 

  33. Fathizadeh, A., Soltani, K., Medenica, M. & Lorincz, A.L. Pigmentary changes in Seckel's syndrome. J. Am. Acad. Dermatol. 1, 52–54 (1979).

    Article  CAS  PubMed  Google Scholar 

  34. Griffith, E. et al. Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat. Genet. 40, 232–236 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Goodship, J. et al. Autozygosity mapping of a Seckel syndrome locus to chromosome 3q22. 1-q24. Am. J. Hum. Genet. 67, 498–503 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fowden, A.L., Giussani, D.A. & Forhead, A.J. Intrauterine programming of physiological systems: causes and consequences. Physiology (Bethesda) 21, 29–37 (2006).

    CAS  Google Scholar 

  37. Fowden, A.L., Forhead, A.J., Coan, P.M. & Burton, G.J. The placenta and intrauterine programming. J. Neuroendocrinol. 20, 439–450 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Barker, D. The fetal origins of adult disease. Proc. R. Soc. Lond. B 262, 37–43 (1995).

    Article  CAS  Google Scholar 

  39. Murphy, D.P. Ovarian radiation—its effect on the health of subsequent children. Review of the literature, experimental and clinical, with a report of 320 human pregnancies. Surg. Gynecol. Obstet. 47, 201–215 (1928).

    Google Scholar 

  40. Schmidt, S.L. & Lent, R. Effects of prenatal irradiation on the development of cerebral cortex and corpus callosum of the mouse. J. Comp. Neurol. 264, 193–204 (1987).

    Article  CAS  PubMed  Google Scholar 

  41. Rodier, F., Campisi, J. & Bhaumik, D. Two faces of p53: aging and tumor suppression. Nucleic Acids Res. 35, 7475–7484 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. el-Deiry, W.S. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Sidi, S. et al. Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3. Cell 133, 864–877 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang, Q. et al. UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J. Natl. Cancer Inst. 88, 956–965 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Viale, A. et al. Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature 457, 51–56 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Matheu, A. et al. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448, 375–379 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Brown, E.J. & Baltimore, D. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14, 397–402 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu, Q. et al. Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint. Genes Dev. 14, 1448–1459 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1–7 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Murga, M. et al. Global chromatin compaction limits the strength of the DNA damage response. J. Cell Biol. 178, 1101–1108 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M. Serrano and A. Ramiro for critical comments on the manuscript. We also thank S.P. Jackson for his help with the PIKK inhibitors and A. Garcia for cytometry. M.M. is supported by a Ramón y Cajal contract from the Spanish Ministry of Science (RYC-2003-002731) and from a grant from Fondo de Investigaciones Sanitarias (PI080220). Work in O.F.-C.'s laboratory is supported by grants from the Spanish Ministry of Science (RYC-2003-002731, CSD2007-00017 and SAF2008-01596), European Molecular Biology Organization Young Investigator Programme, European Research Council (ERC-210520) and Epigenome Network of Excellence.

Author information

Authors and Affiliations

Authors

Contributions

O.F.-C. designed the study and experiments and wrote the paper. M.M. performed most of the experiments presented. M.F.M. and R.S. helped in the analysis of Seckel MEFs and embryos. S.B. and A.N. performed HSC and chromosomal breakage analyses. F.M. helped with the whole body Imaging. M.C. helped with the pathology. Y.L. and P.J.M. performed the analyses of the brains.

Corresponding authors

Correspondence to Matilde Murga or Oscar Fernandez-Capetillo.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 3958 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Murga, M., Bunting, S., Montaña, M. et al. A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging. Nat Genet 41, 891–898 (2009). https://doi.org/10.1038/ng.420

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.420

This article is cited by

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