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Open Access Research article

Effect of hydroxyurea on the promoter occupancy profiles of tumor suppressor p53 and p73

Vera Huang135, Xin Lu346, Yong Jiang237 and Jean YJ Wang123*

Author Affiliations

1 Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0820, USA

2 Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0820, USA

3 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA

4 Department of Family and Preventive Medicine, Division of Bioinformatics and Biostatistics, University of California, San Diego, La Jolla, CA 92093, USA

5 Current address: Department of Urology and Helen-Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA

6 Current address: Abbott Laboratories, 100 Abbott Park Road, North Chicago, IL 60063, USA

7 Current address: Wintherix LLC, 10578 Science Center Drive, CB-7, Ste 1133, San Diego, CA 92121, USA

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BMC Biology 2009, 7:35  doi:10.1186/1741-7007-7-35

Published: 26 June 2009

Abstract

Background

The p53 tumor suppressor and its related protein, p73, share a homologous DNA binding domain, and mouse genetics studies have suggested that they have overlapping as well as distinct biological functions. Both p53 and p73 are activated by genotoxic stress to regulate an array of cellular responses. Previous studies have suggested that p53 and p73 independently activate the cellular apoptotic program in response to cytotoxic drugs. The goal of this study was to compare the promoter-binding activity of p53 and p73 at steady state and after genotoxic stress induced by hydroxyurea.

Results

We employed chromatin immunoprecipitation, the NimbleGen promoter arrays and a model-based algorithm for promoter arrays to identify promoter sequences enriched in anti-p53 or anti-p73 immunoprecipitates, either before or after treatment with hydroxyurea, which increased the expression of both p53 and p73 in the human colon cancer cell line HCT116-3(6). We calculated a model-based algorithm for promoter array score for each promoter and found a significant correlation between the promoter occupancy profiles of p53 and p73. We also found that after hydroxyurea treatment, the p53-bound promoters were still bound by p73, but p73 became associated with additional promoters that that did not bind p53. In particular, we showed that hydroxyurea induces the binding of p73 but not p53 to the promoter of MLH3, which encodes a mismatch repair protein, and causes an up-regulation of the MLH3 mRNA.

Conclusion

These results suggest that hydroxyurea exerts differential effects on the promoter-binding functions of p53 and p73 and illustrate the power of model-based algorithm for promoter array in the analyses of promoter occupancy profiles of highly homologous transcription factors.