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An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

Oncogene volume 29, pages 2659–2671 (2010)Cite this article

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Abstract

There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.

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Acknowledgements

We are grateful to Mien-Chi Hung for critical discussions. We thank Xiangwei He and Qi Gao for assistance in microscopic imaging; Tao Jiang and Qian Li for technical assistance. This study was supported in part by the following grants: Tianjin Medical University Cancer Institute and Hospital Start-up 08Y01 (to Z Li); Ministry of Science and Technology of China 973-program Concept Award 2009CB526407 (to Z Li); Tianjin Municipal Science and Technology Foundation (to Z Li); Department of defense of United States FG02-03ER63630 (to A Balmain); IZKF Jena Start-up S16 (to T Liehr).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Key Laboratory of Ministry of Education for Breast Cancer Prevention and Treatment, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Z Li, X Fan & X Zhang

  2. Department of Gynecologic Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Q Zhang & K H Lu

  3. Cancer Research Institute, University of California at San Francisco, San Francisco, CA, USA

    J-H Mao & A Balmain

  4. Institute for Human Genetics and Anthropology, Jena, Germany

    A Weise, K Mrasek & T Liehr

  5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    W-W Cai

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Correspondence to Z Li or W-W Cai.

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Li, Z., Zhang, Q., Mao, JH. et al. An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis. Oncogene 29, 2659–2671 (2010). https://doi.org/10.1038/onc.2010.19

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