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Nucleic Acids Research Advance Access originally published online on March 18, 2009
Nucleic Acids Research 2009 37(9):2962-2973; doi:10.1093/nar/gkp180
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Nucleic Acids Research, 2009, Vol. 37, No. 9 2962-2973
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gene Regulation, Chromatin and Epigenetics

Heat shock factor-1 modulates p53 activity in the transcriptional response to DNA damage

Ian R. Logan1, Hesta V. McNeill1, Susan Cook1, Xiaohong Lu1, David W. Meek2, Frances V. Fuller-Pace3, John Lunec1 and Craig N. Robson1,*

1Northern Institute for Cancer Research, Newcastle University, Paul O’Gorman Building, Medical School, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK, 2Molecular Signalling Group and 3Cancer Biology Group, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK

*To whom correspondence should be addressed. Tel: +44 191 246 4300; Fax: +44 191 246 4301; Email: c.n.robson{at}ncl.ac.uk

Received November 17, 2008. Revised March 4, 2009. Accepted March 4, 2009.

Here we define an important role for heat shock factor 1 (HSF1) in the cellular response to genotoxic agents. We demonstrate for the first time that HSF1 can complex with nuclear p53 and that both proteins are co-operatively recruited to p53-responsive genes such as p21. Analysis of natural and synthetic cis elements demonstrates that HSF1 can enhance p53-mediated transcription, whilst depletion of HSF1 reduces the expression of p53-responsive transcripts. We find that HSF1 is required for optimal p21 expression and p53-mediated cell-cycle arrest in response to genotoxins while loss of HSF1 attenuates apoptosis in response to these agents. To explain these novel properties of HSF1 we show that HSF1 can complex with DNA damage kinases ATR and Chk1 to effect p53 phosphorylation in response to DNA damage. Our data reveal HSF1 as a key transcriptional regulator in response to genotoxic compounds widely used in the clinical setting, and suggest that HSF1 will contribute to the efficacy of these agents.


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