Role of the mammalian SWI/SNF chromatin remodeling complex in the cellular response to UV damage.
Mammalian cells exhibit complex cellular responses to DNA damage, including cell cycle arrest, DNA repair and apoptosis. Defects in any one of these responses can result in carcinogenesis. Absence of the chromatin remodeling complex Swi/Snf is found in many instances of cancer, and we have investigated its role in the UV damage response. The human carcinoma cell line SW13 is deficient in Swi/Snf and is very sensitive to UV radiation. In contrast, SW13 cells with ectopic Brg1 expression regain active Swi/Snf and become significantly more resistant to UV radiation. Sensitivity to UV light correlates well with dramatic UV induced apoptosis in SW13 cells, but not in SW13 cells expressing Brg1. We show that SW13 cells synchronized at the G(1)/S border progress into S phase after UV irradiation, and this checkpoint deficiency is corrected after Brg1 expression is restored. Interestingly, Brg1 expression in SW13 cells restores expression of two DNA damage responsive genes, Gadd45a and p21. Furthermore, Gadd45a induction and p21 degradation were observed in the Brg1-expressing SW13 cells after UV irradiation. Our findings demonstrate that Swi/Snf protects cells against deleterious consequences of UV induced DNA damage. These results also indicate that Swi/Snf may modulate checkpoint activation after UV damage via regulation of the two PCNA-binding proteins Gadd45a and p21.
Gong
Feng
F
Biochemistry and Biophysics, School of Molecular Biosciences, Washington State University, Pullman, Washington, USA. fgong@med.miami.edu
Fahy
Deirdre
D
Liu
Hong
H
Wang
Weidong
W
Smerdon
Michael J
MJ
D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014466:Ultraviolet Rays; D054462:p21-Activated Kinases / Q000378:metabolism; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004265:DNA Helicases; D017931:DNA Primers; D009687:Nuclear Proteins; D014157:Transcription Factors; D054462:p21-Activated Kinases; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C445179:SWI-SNF-B chromatin-remodeling complex; C084108:SMARCA4 protein, human