Ultraviolet light exposure triggers nuclear accumulation of p21(WAF1) and accelerated senescence in human normal and nucleotide excision repair-deficient fibroblast strains.
Induction of the p21(WAF1) protein (hereafter called p21) following genotoxic stress is known to inhibit proliferating cell nuclear antigen (PCNA)-dependent DNA repair, downregulate apoptosis, and trigger a sustained growth-arrested phenotype called accelerated senescence. Studies with immortalized human and murine cell lines have revealed that exposure to ultraviolet light (UVC; 254 nm) results in the degradation of p21 to facilitate DNA repair and promote cell survival, or may lead to apoptotic cell death. The objective of the present study was to determine whether exposure of non-transformed human fibroblast strains to relatively low fluences of UVC (i.e., fluences typically used in the clonogenic survival assay) might induce sustained nuclear accumulation of p21, leading to accelerated senescence. We have evaluated the responses of normal human fibroblast (NHF) strains and nucleotide excision repair (NER)-deficient fibroblast strains representing xeroderma pigmentosum (XP) complementation groups A and G and Cockayne syndrome (CS) complementation groups A and B. We report that exposure of NHFs to < or =15 J/m(2) of UVC, and NER-deficient fibroblasts to < or =5 J/m(2) of UVC, results in sustained nuclear accumulation of p21 and growth arrest through accelerated senescence. With each fibroblast strain examined, exposure to UVC fluences that resulted in approximately 90% loss of clonogenic potential triggered significant (>60%) accelerated senescence, but only marginal (<5%) apoptosis. We conclude that nuclear accumulation of p21 accompanied by accelerated senescence may be an integral component of the response of human fibroblasts to UVC-induced DNA damage, irrespective of their DNA repair capabilities.
Mirzayans
Razmik
R
Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta T6G 1Z2, Canada. razmikm@cancerboard.ab.ca
Scott
April
A
Andrais
Bonnie
B
Pollock
Scott
S
Murray
David
D
D017209:Apoptosis / Q000528:radiation effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism* / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D016922:Cellular Senescence / Q000528:radiation effects*; D003114:Colony-Forming Units Assay; D017077:Culture Media, Conditioned; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D004260:DNA Repair / Q000528:radiation effects*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000528:radiation effects; D006131:Growth Inhibitors / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000528:radiation effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
D017077:Culture Media, Conditioned; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006131:Growth Inhibitors; C468783:H2AX protein, human; D006657:Histones; D012333:RNA, Messenger; D001973:Bromodeoxyuridine