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p21 Waf1/Cip1 plays a critical role in modulating senescence through changes of DNA methylation
Author(s) -
Zheng Quan Hui,
Ma Li Wei,
Zhu Wei Guo,
Zhang Zong Yu,
Tong Tan Jun
Publication year - 2006
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20838
Subject(s) - dna methylation , methylation , methyltransferase , senescence , epigenetics , biology , dna damage , dnmt1 , microbiology and biotechnology , dna methyltransferase , dna , gene , gene expression , genetics
It has been reported that genomic DNA methylation decreases gradually during cell culture and an organism's aging. However, less is known about the methylation changes of age‐related specific genes in aging. p21 Waf1/Cip1 and p16 INK4a are cyclin‐dependent kinase (Cdk) inhibitors that are critical for the replicative senescence of normal cells. In this study, we show that p21 Waf1/Cip1 and p16 INK4a have different methylation patterns during the aging process of normal human 2BS and WI‐38 fibroblasts. p21 Waf1/Cip1 promoter is gradually methylated up into middle‐aged fibroblasts but not with senescent fibroblasts, whereas p16 INK4a is always unmethylated in the aging process. Correspondently, the protein levels of DNA methyltransferase 1 (DNMT1) and DNMT3a increase from young to middle‐aged fibroblasts but decrease in the senescent fibroblasts, while DNMT3b decreases stably from young to senescent fibroblasts. p21 Waf1/Cip1 promoter methylation directly represses its expression and blocks the radiation‐induced DNA damage‐signaling pathway by p53 in middle‐aged fibroblasts. More importantly, demethylation by 5‐aza‐CdR or DNMT1 RNA interference (RNAi) resulted in an increased p21 Waf1/Cip1 level and premature senescence of middle‐aged fibroblasts demonstrated by cell growth arrest and high β‐Galactosidase expression. Our results suggest that p21 Waf1/Cip1 but not p16 INK4a is involved in the DNA methylation mediated aging process. p21 Waf1/Cip1 promoter methylation may be a critical biological barrier to postpone the aging process. J. Cell. Biochem. 98: 1230–1248, 2006. © 2006 Wiley‐Liss, Inc.