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hHR23B is required for genotoxic-specific activation of p53 and apoptosis

Oncogene volume 26, pages 1231–1237 (2007)Cite this article

Abstract

Rad23 proteins function in both DNA repair and protein stability regulation. As ubiquitinated forms of p53 are stabilized after DNA damage in concert with p53 functional activation, and human Rad23 proteins (hHR23A and B) regulate p53 stability in unstressed cells, the role of hHR23B in post-genotoxin regulation of p53 was investigated. Depletion of hHR23B by specific short interfering RNA before genotoxic exposure attenuated p53, p21 and bax induction, abrogated the accumulation of ubiquitinated p53 and suppressed apoptosis. Expression of ubiquitin derivatives with all lysines mutated except K48 or K63 demonstrated that K48-linked p53-ubiquitin conjugates were specifically induced after DNA damage. hHR23B, along with native and ubiquitinated p53, accumulated in chromatin after genotoxic exposure, and the accumulation of ubiquitinated p53 in chromatin was prevented by hHR23B depletion. Chromatin immunoprecipitation analysis demonstrated that hHR23B and p53 both localized to the p21 promoter shortly after DNA damage. hHR23B thus plays a critical role in the activation and function of p53 after specific genotoxic exposures.

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Acknowledgements

We thank V Sharma for assistance with ChIP assays. This work was supported by CA107532 from NCI.

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Author notes

  1. C Brignone

    Present address: Immutep SA, Faculté de Pharmacie 5, rue Jean Baptiste Clement, 92296, Chatenay-Malabry, France

Authors and Affiliations

  1. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA

    M Kaur, M Pop, D Shi, C Brignone & S R Grossman

  2. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    S R Grossman

  3. Gastrointestinal Cancer Program, University of Massachusetts Medical School and UMass Memorial Cancer Center, Worcester, MA, USA

    S R Grossman

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  1. M Kaur
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  2. M Pop
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  3. D Shi
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  5. S R Grossman
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Corresponding author

Correspondence to S R Grossman.

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

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Kaur, M., Pop, M., Shi, D. et al. hHR23B is required for genotoxic-specific activation of p53 and apoptosis. Oncogene 26, 1231–1237 (2007). https://doi.org/10.1038/sj.onc.1209865

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