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Molecular and Cellular Biology, March 1999, p. 1673-1685, Vol. 19, No. 3
0270-7306/99

Gadd45, a p53-Responsive Stress Protein, Modifies DNA Accessibility on Damaged Chromatin

France Carrier,1,* Philippe T. Georgel,2,dagger Philippe Pourquier,3 Mellissa Blake,1 H. Udo Kontny,1 Michael J. Antinore,1 Marzia Gariboldi,3 Timothy G. Myers,3 John N. Weinstein,3 Yves Pommier,3 and Albert J. Fornace Jr.1

Laboratory of Biological Chemistry,1 Laboratory of Biochemistry,2 and Laboratory of Molecular Pharmacology,3 National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255

Received 6 August 1998/Returned for modification 1 October 1998/Accepted 8 December 1998

This report demonstrates that Gadd45, a p53-responsive stress protein, can facilitate topoisomerase relaxing and cleavage activity in the presence of core histones. A correlation between reduced expression of Gadd45 and increased resistance to topoisomerase I and topoisomerase II inhibitors in a variety of human cell lines was also found. Gadd45 could potentially mediate this effect by destabilizing histone-DNA interactions since it was found to interact directly with the four core histones. To evaluate this possibility, we investigated the effect of Gadd45 on preassembled mononucleosomes. Our data indicate that Gadd45 directly associates with mononucleosomes that have been altered by histone acetylation or UV radiation. This interaction resulted in increased DNase I accessibility on hyperacetylated mononucleosomes and substantial reduction of T4 endonuclease V accessibility to cyclobutane pyrimidine dimers on UV-irradiated mononucleosomes but not on naked DNA. Both histone acetylation and UV radiation are thought to destabilize the nucleosomal structure. Hence, these results imply that Gadd45 can recognize an altered chromatin state and modulate DNA accessibility to cellular proteins.

* Corresponding author. Present address: School of Medicine University of Maryland at Baltimore, 108 N. Greene St., Baltimore, MD 21201. Phone: (410) 706-5105. Fax: (410) 706-8297. E-mail: fcarr001{at}umaryland.edu.

dagger Present address: University of Rochester, Rochester, NY.

Molecular and Cellular Biology, March 1999, p. 1673-1685, Vol. 19, No. 3
0270-7306/99


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