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BRIT1/MCPH1 links chromatin remodelling to DNA damage response

Nature Cell Biology volume 11, pages 865–872 (2009)Cite this article

Abstract

To detect and repair damaged DNA, DNA-damage-response proteins need to overcome the barrier of condensed chromatin to gain access to DNA lesions1. ATP-dependent chromatin remodelling is one of the fundamental mechanisms used by cells to relax chromatin in DNA repair2,3. However, the mechanism mediating their recruitment to DNA lesions remains largely unknown. BRIT1 (also known as MCPH1) is an early DNA-damage-response protein that is mutated in human primary microcephaly4,5,6,7,8. Here we report a previously unknown function of BRIT1 as a regulator of the ATP-dependent chromatin remodelling complex SWI–SNF in DNA repair. After damage to DNA, BRIT1 increases its interaction with SWI–SNF through ATM/ATR-dependent phosphorylation on the BAF170 subunit. This increase in binding affinity provides a means by which SWI–SNF can be specifically recruited to and maintained at DNA lesions. Loss of BRIT1 causes impaired chromatin relaxation as a result of decreased association of SWI–SNF with chromatin. This explains the decreased recruitment of repair proteins to DNA lesions and the reduced efficiency of repair in BRIT1-deficient cells, resulting in impaired cell survival after DNA damage. Our findings therefore identify BRIT1 as a key molecule that links chromatin remodelling with response to DNA damage in the control of DNA repair, and its dysfunction contributes to human disease.

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Figure 1: BRIT1 interacts with the SWI–SNF complex.
Figure 2: Interaction between BRIT1 and SWI–SNF is responsive to DNA damage.
Figure 3: BRIT1 depletion impairs DNA DSB repair.
Figure 4: BRIT promotes the function of SWI–SNF.
Figure 5: BRIT1 promotes DNA repair and chromatin relaxation in two human MCPH lymphoblastoid cell lines (MCPH 1 and MCPH 2).

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Acknowledgements

We thank S. Rosenberg, X. Shen and F. Meric-Bernstam for critical reading of the manuscript; S. Deming for proofreading it; M. Jasin for reagents; E. Griffith for identifying the mutation in the MCPH no. 2 cell line; and the core facilities of the M. D. Anderson Cancer Center for mass spectrometry and fluorescence-activated cell sorting. This work was supported by a grant from the National Cancer Institute (R01CA112291) and an American Cancer Society Research Scholar Award to S.Y.L.

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Authors and Affiliations

  1. Department of Systems Biology, Unit 950, The University of Texas M. D. Anderson Cancer Center, Houston, 77054, Texas, USA

    Guang Peng, Eun-Kyoung Yim, Hui Dai, Mei-Ren Pan, Ruozhen Hu & Shiaw-Yih Lin

  2. MRC Human Genetics Unit, Western General Hospital, EH4 2XU, Edinburgh, UK

    Andrew P. Jackson

  3. Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, PO Box 9101, The Netherlands

    Ineke van der Burgt

  4. Department of Surgery, Baylor College of Medicine, Houston, 77030, Texas, USA

    Kaiyi Li

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  1. Guang Peng
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Contributions

S.-Y.L. conceived the project. G.P. and S.-Y.L. designed the experiments and wrote the manuscript. G.P. performed the experimental studies with technical assistance from H.D., E.-K.Y., M.-R.P. and R.H. on immunofluorescent staining, subcloning and western blotting. G.P. and K.L. performed data analysis. A.P.J. and I.v.d.B. contributed molecularly characterized cell lines from patients with MCPH1. A.P.J. also provided thoughtful comments on the manuscript.

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Correspondence to Shiaw-Yih Lin.

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Peng, G., Yim, EK., Dai, H. et al. BRIT1/MCPH1 links chromatin remodelling to DNA damage response. Nat Cell Biol 11, 865–872 (2009). https://doi.org/10.1038/ncb1895

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