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Molecular and Cellular Biology, May 2000, p. 3705-3714, Vol. 20, No. 10
Division of Basic Science, National Cancer
Institute,1 and National Institute of
Diabetes, Digestive, and Kidney Diseases,4
National Institutes of Health, Bethesda, Maryland 20892;
Department of Biological Sciences, Stanford University,
Stanford, California 943052; and Indiana
University Cancer Center/Walther Oncology Center and Department of
Microbiology, Indiana University School of Medicine, Indianapolis,
Indiana 462023
Received 14 January 2000/Returned for modification 17 February
2000/Accepted 22 February 2000
Human cells lacking functional p53 exhibit a partial deficiency in
nucleotide excision repair (NER), the pathway for repair of UV-induced
DNA damage. The global genomic repair (GGR) subpathway of NER, but not
transcription-coupled repair (TCR), is mainly affected by p53 loss or
inactivation. We have utilized mouse embryo fibroblasts (MEFs)
lacking p53 genes or downstream effector genes of the p53
pathway, gadd45 (Gadd45a) or p21
(Cdkn1a), as well as MEFs lacking both gadd45
and p21 genes to address the potential contribution of
these downstream effectors to p53-associated DNA repair. Loss of
p53 or gadd45 had a pronounced effect on GGR, while p21 loss had only a marginal effect, determined by
measurements of repair synthesis (unscheduled DNA synthesis), by
immunoassays to detect removal of UV photoproducts from genomic DNA,
and by assays determining strand-specific removal of CPDs from the
mouse dhfr gene. Taken together, the evidence suggests a
role for Gadd45, but relatively little role for p21, in DNA repair
responses to UV radiation. Recent evidence suggests that Gadd45 binds
to UV-damaged chromatin and may affect lesion accessibility. MEFs
lacking p53 or gadd45 genes exhibited decreased
colony-forming ability after UV radiation and cisplatin compared
to wild-type MEFs, indicating their sensitivity to DNA damage.
We provide evidence that Gadd45 affects chromatin remodelling of
templates concurrent with DNA repair, thus indicating that Gadd45 may
participate in the coupling between chromatin assembly and DNA repair.
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
p53-Mediated DNA Repair Responses to UV Radiation: Studies of
Mouse Cells Lacking p53, p21, and/or
gadd45 Genes

*
Corresponding author. Present address: Indiana
University Cancer Center, Department of Microbiology and Walther
Oncology Center, R4-155, Indiana University School of Medicine,
Indianapolis, IN 46202.
Present address: Departments of Medicine and Genetics, Division of
Oncology, Stanford University School of Medicine, Stanford, CA 94305.
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