Article | Published:

Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation

Nature Cell Biology volume 17, pages 11581168 (2015) | Download Citation

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Abstract

Histone methylation regulates DNA repair. However, the mechanisms that underlie the regulation of histone methylation during this repair remain to be further defined. Here, we show that exposure to ionizing radiation induces DNA-PK-dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions. Locally generated fumarate inhibits KDM2B histone demethylase activity, resulting in enhanced dimethylation of histone H3 Lys 36; in turn, this increases the accumulation of the Ku70-containing DNA-PK at DSB regions for non-homologous end-joining DNA repair and cell survival. These findings reveal a feedback mechanism that underlies DNA-PK regulation by chromatin-associated fumarase and an instrumental function of fumarase in regulating histone H3 methylation and DNA repair.

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  • 09 April 2018

    In the version of this Article originally published, the authors mistakenly used the same images for three different time points in Fig. 2d: images for 24 h post-IR WT were also used for 0 h post-IR WT (top row, left panels) and for 1 h post-IR, T236A mutant (2nd row from the top, right panels). The correct images from these experiments have now been inserted in the figure in all online versions of the Article. In addition, results from this experiment and from two additional independent experiments have been uploaded to Figshare and the sentence 'Additional repeats of this experiment have been uploaded to Figshare28.' has been added to the figure legend to highlight this fact. The Figshare doi has been added as reference 28. The new reference and corrected Fig. 2d are shown below. 28. Jiang, Y. et al. FH pT236-gammaH2AX-1-2-3.tif. Figshare https://doi.org/10.6084/m9.figshare.5867907 (2018).

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Acknowledgements

We thank D. Hawke, B.-F. Pan and M.-B. Hossain at MD Anderson for their technical assistance and A. Sutton for her critical reading of this manuscript. This work was supported by National Cancer Institute grants 2R01CA109035 (Z.L.) and 1R0CA169603 (Z.L.), National Institute of Neurological Disorders and Stroke grant 1R01NS089754 (Z.L.), the MD Anderson Cancer Center Support Grant CA016672, James S. McDonnell Foundation 21st Century Science Initiative in Brain Cancer Research Award 220020318 (Z.L.), 2P50CA127001 (Brain Cancer SPORE), a Sister Institution Network Fund from The University of Texas MD Anderson Cancer Center (Z.L.), and the Odyssey Fellowship from MD Anderson (Y.J.). Z.L. is a R. E. Rutherford Distinguished Professor.

Author information

Affiliations

  1. Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Yuhui Jiang
    • , Xu Qian
    • , Yugang Wang
    • , Xinjian Li
    • , Rui Liu
    • , Yan Xia
    •  & Zhimin Lu
  2. The Institute of Cell Metabolism, Shanghai Key Laboratory of Pancreatic Cancer, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China

    • Yuhui Jiang
  3. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Jianfeng Shen
    •  & Guang Peng
  4. State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China

    • Rui Liu
    •  & Qianming Chen
  5. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Shiaw-Yih Lin
  6. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Zhimin Lu
  7. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA

    • Zhimin Lu

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Contributions

This study was conceived by Z.L.; Z.L. and Y.J. designed the study; Y.J., X.Q., J.S., Y.W., X.L., R.L. and Y.X. performed experiments; Q.C., G.P. and S.-Y.L. provided reagents and conceptual advice; Z.L. wrote the paper with comments from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Zhimin Lu.

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https://doi.org/10.1038/ncb3209

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