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Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response

Oncogene volume 27, pages 931–941 (2008)Cite this article

An Erratum to this article was published on 13 March 2008

Abstract

The histone acetyltransferase TIP60 regulates the DNA damage response following genotoxic stress by acetylating histone and remodeling chromatin. However, the molecular mechanisms underlying the TIP60-dependent response to UV-induced DNA damage remain poorly understood. To systematically analyse proteins that regulate TIP60 activity in response to UV irradiation, we performed a proteomic analysis of proteins selectively bound to TIP60 in response to UV irradiation using mass spectrometry and identified a novel regulatory mechanism by which TIP60 orchestrates transcriptional activation of p53-dependent checkpoint response in UV-irradiated cells. The initial step of this pathway involves UV-induced association of TIP60 with SUMO-conjugation enzymes and site-specific sumoylation of TIP60 at lysines 430 and 451 via Ubc9. This sumoylation initiates the relocation of TIP60 from nucleoplasm to the promyelocytic leukemia body, which is essential for the UV-irradiated DNA damage repair response via a p53-dependent pathway. Significantly, inhibition of TIP60 sumoylation by overexpression of non-sumoylatable mutant abrogates the p53-dependent DNA damage response, demonstrating the importance of TIP60 sumoylation in response to UV irradiation. Our biochemical characterization demonstrated that the sumoylation of TIP60 augments its acetyltransferase activity in vitro and in vivo. Thus, this study shed new light on the function and regulation of TIP60 activity in UV-irradiated DNA damage response.

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Abbreviations

HAT:

histone acetyltransferase

MYST, MOZ, Ybf21/Sas3, Sas2 and Tip60 acetyltransferase family; NB:

nuclear body

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Acknowledgements

This work was supported by grants from Chinese 973 project (2002CB713700 and 2006CBOF0503), Chinese Academy of Sciences (KSCX1-YW-R65), Chinese Natural Science Foundation (39925018, 30270293, 90508002) and National Institutes of Health (DK56292). SER and XY are GCC Eminent Scholars. The facilities used were partially supported by NIH/NCRR/RCM1 grant G-12-RR03034.

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Author notes

  1. Z Cheng and Y Ke: These authors contributed equally to this work.

Authors and Affiliations

  1. C,

    Z Cheng, Y Ke, F Wang, H Wang, K Ahmed, Z Liu, H Yan, J Liu, Y Xue, C Jin & X Yao

  2. ellular Dynamics, Hefei National Laboratory, Hefei, China

    Z Cheng, Y Ke, F Wang, H Wang, K Ahmed, Z Liu, H Yan, J Liu, Y Xue, C Jin & X Yao

  3. Cancer Biology Program, Morehouse School of Medicine, Atlanta, GA, USA

    X Ding, F Wang, F Aikhionbare, M Powell & S E Reddy

  4. Department of Medicine, Beijing University of Chinese Medicine, Beijing, China

    X Ding & X Yao

  5. Department of Hematology, Zhejiang University, Hongzhou, China

    Y Xu & H Huang

  6. Laboratory of Protein Chemistry, Hunan Normal University, Changsha, China

    S Liang

  7. Department of Endocrinology, Fudan University, Shanghai, China

    R Hu

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  1. Z Cheng
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Corresponding author

Correspondence to X Yao.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Cheng, Z., Ke, Y., Ding, X. et al. Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response. Oncogene 27, 931–941 (2008). https://doi.org/10.1038/sj.onc.1210710

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