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Involvement of a chromatin remodeling complex in damage tolerance during DNA replication

Nature Structural & Molecular Biology volume 16, pages 1167–1172 (2009)Cite this article

Abstract

ATP-dependent chromatin remodeling complexes have been shown to participate in DNA replication in addition to transcription and DNA repair. However, the mechanisms of their involvement in DNA replication remain unclear. Here, we reveal a specific function of the yeast INO80 chromatin remodeling complex in the DNA damage tolerance pathways. Whereas INO80 is necessary for the resumption of replication at forks stalled by methyl methane sulfonate (MMS), it is not required for replication fork collapse after treatment with hydroxyurea (HU). Mechanistically, INO80 regulates DNA damage tolerance during replication through modulation of PCNA (proliferating cell nuclear antigen) ubiquitination and Rad51-mediated processing of recombination intermediates at impeded replication forks. Our findings establish a mechanistic link between INO80 and DNA damage tolerance pathways, indicating that chromatin remodeling is important for accurate DNA replication.

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Figure 1: INO80 is dispensable for fork stabilization after HU treatment.
Figure 2: INO80 is required to restart MMS-stalled replication forks.
Figure 3: INO80 is involved in the DNA damage tolerance pathway.
Figure 4: INO80 is required for Rad51-dependent recombination intermediates formation after MMS treatment.

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Acknowledgements

We thank E. Schwob (IGMM) and J. Rouse (MRC) for strains; H. Ulrich (Cancer UK) for strains and protocols; M.A. Osley (University of New Mexico) for protocols; P. Sung (Yale University) for Rad51 antibody; J. Delrow and R. Basom (Fred Hutchinson Cancer Research Center, FHCRC) for microarray analysis; K. Claypool and S. Hasley (M.D. Anderson Cancer Center (MDACC)) for technical assistance; and members of the Shen lab for comments on the manuscript. This work was supported by funds and grants from MDACC, ACS (RSG-05-060-01-GMC) and the National Institute of Environmental Health Sciences (ES07784) to X.S. (MDACC), from the Rosalie B. Hite Fellowship to K.B.F. (MDACC), from the Fondation Recherche Medicale, the Centre National de la Recherche Scientifique, the Agence Nationale de la Recherche and the Institut National du Cancer to P.P.; by an ARC fellowship to C.A. (CNRS); and by a grant from the US National Institutes of Health (GM71729) to Z.Z. K.S. was supported by a grant of the Cell Innovation Project and Grant-in-Aid for Scientific Research (S) from the Ministry of Education Science and Sports (MEXT), Japan. Y.K. is a Global Center of Excellence (GCOE) research associate.

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Author notes

  1. Karina B Falbo, Constance Alabert and Yuki Katou: These authors contributed equally.

Authors and Affiliations

  1. Department of Carcinogenesis, Science Park Research Division, M.D. Anderson Cancer Center, Smithville, Texas, USA

    Karina B Falbo, Tammy Wehr, Jing Xiao & Xuetong Shen

  2. Institute of Human Genetics, CNRS UPR 1142, Montpellier, France

    Constance Alabert & Philippe Pasero

  3. Gene Research Center, Tokyo Institute of Technology, Midori-ku, Yokohama, Japan

    Yuki Katou & Katsu Shirahige

  4. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Su Wu & Yang Shi

  5. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    Junhong Han & Zhiguo Zhang

  6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    Xiangwei He

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Contributions

K.B.F. and X.S. designed the study with contributions from X.H., S.W. and Y.S.; K.B.F., C.A., P.P., Y.K., K.S., J.H. and Z.Z. carried out experiments; T.W. and J.X. provided technical assistance. K.B.F. and X.S. wrote the paper.

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Correspondence to Xuetong Shen.

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Falbo, K., Alabert, C., Katou, Y. et al. Involvement of a chromatin remodeling complex in damage tolerance during DNA replication. Nat Struct Mol Biol 16, 1167–1172 (2009). https://doi.org/10.1038/nsmb.1686

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