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

Nature Genetics volume 41, pages 891–898 (2009)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Matilde Murga, Maria F Montaña, Rebeca Soria & Oscar Fernandez-Capetillo

  2. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Samuel Bunting & Andre Nussenzweig

  3. Molecular Imaging Unit, CNIO, Madrid, Spain

    Francisca Mulero

  4. Comparative Pathology Unit, CNIO, Madrid, Spain

    Marta Cañamero

  5. Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Youngsoo Lee & Peter J McKinnon

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  1. Matilde Murga
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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.

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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

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