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A YY1–INO80 complex regulates genomic stability through homologous recombination–based repair

Nature Structural & Molecular Biology volume 14, pages 1165–1172 (2007)Cite this article

Abstract

DNA damage repair is crucial for the maintenance of genome integrity and cancer suppression. We found that loss of the mouse transcription factor YY1 resulted in polyploidy and chromatid aberrations, which are signatures of defects in homologous recombination. Further biochemical analyses identified a YY1 complex comprising components of the evolutionarily conserved INO80 chromatin-remodeling complex. Notably, RNA interference–mediated knockdown of YY1 and INO80 increased cellular sensitivity toward DNA-damaging agents. Functional assays revealed that both YY1 and INO80 are essential in homologous recombination–based DNA repair (HRR), which was further supported by the finding that YY1 preferentially bound a recombination-intermediate structure in vitro. Collectively, these observations reveal a link between YY1 and INO80 and roles for both in HRR, providing new insight into mechanisms that control the cellular response to genotoxic stress.

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Figure 1: Loss of YY1 results in polyploidy and chromosome structural aberrations.
Figure 2: YY1 associates with mammalian Ino80 complex.
Figure 3: YY1 interacts with INO80 subunits in vitro and in vivo.
Figure 4: Knockdown of TIP49B and INO80 leads to UV hypersensitivity.
Figure 5: Impaired homology-directed repair of a chromosomal DSB in YY1- and INO80-deficient 293T and HT-1080 cell lines.
Figure 6: YY1 binds a recombination-intermediate structure in vitro. (a) Purified YY1 complex was incubated with biotinylated Holliday-junction DNA (probe), and the binding reactions were resolved on 4% nondenaturing PAGE gels.

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Acknowledgements

We thank members of the Shi laboratory for suggestions and helpful discussions; R. Scully and A. Xie (Harvard Institute of Medicine) for reagents and discussion; M.D. Cole (Dartmouth University), Y. Nakatani (Dana Farber Cancer Institute), W. Harper (Harvard Medical School) and J. Lieberman (Harvard Medical School) for antibodies and constructs; and G. Sui (Wake Forest University) and Y. Li (Dana Farber Cancer Institute) for technical assistance. pET-Flag-TIP49A and pET-Flag-TIP49B were from T.-a. Tamura (Chiba University); pCMV-Flag-BAF53 and anti-BAF53 were from M.D. Cole; anti-TIP49B was from Y. Nakatani; anti-TIP49Awas from A. Dutta (Dana Farber Cancer Institute); anti-INO80 was from C. Wu (US National Cancer Institute). This project was supported by a grant from the US National Institutes of Health (GM53874) to Yang Shi.

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  1. Yujiang Shi

    Present address: Present address: Division of Endocrinology, Hypertension and Diabetes, Brigham and Women's Hospital, 221 Longwood Avenue, EBRC 222A, Boston, Massachusetts 02115, USA.,

Authors and Affiliations

  1. Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Su Wu, Yujiang Shi, Peter Mulligan, Frédérique Gay, Huifei Liu, Hank H Qi, Weijia Wang & Yang Shi

  2. Laboratory of Biochemistry, National Cancer Institute, US National Institutes of Health, Building 37, Rood 4C-09, Bethesda, 20892-4255, Maryland, USA

    Joseph Landry & Carl Wu

  3. Department of Molecular and Cellular Biology, Program in Neuroscience, Harvard University, Cambridge, Massachusetts 02138, USA.,

    Ju Lu

  4. Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, 87131, New Mexico, USA

    Jac A Nickoloff

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Wu, S., Shi, Y., Mulligan, P. et al. A YY1–INO80 complex regulates genomic stability through homologous recombination–based repair. Nat Struct Mol Biol 14, 1165–1172 (2007). https://doi.org/10.1038/nsmb1332

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