The cell cycle inhibitor p21waf1 binds to the myc and cdc25A promoters upon DNA damage and induces transcriptional repression.
In addition to its function as a cyclin-dependent kinase (cdk) inhibitor, p21waf1 fulfills additional roles involved in DNA replication and transcriptional regulation that could also contribute to cell cycle arrest. In this study, we have shown that p21waf1 functions as a transcriptional repressor of the myc and cdc25A genes. Ectopic expression of the cell cycle inhibitor down-modulates myc and cdc25A transcription but has no effect on cdk4 levels. Using chromatin immunoprecipitation, we found that p21waf1 is recruited to the promoters of these two genes together with the STAT3 and E2F1 transcription factors. Its presence on DNA is associated with an inhibition of the recruitment of the p300 histone acetylase and with a down-regulation of histone H4 acetylation. The same effect was also observed following DNA damage because topoisomerase inhibitors such as sn38 or doxorubicin also induce the association of p21waf1 with DNA. Following transcriptional repression of the myc and cdc25A genes, cells were arrested in the fraction with 4 N DNA content. By contrast, the expression of these two genes remains elevated in the absence of the cell cycle inhibitor, and p21waf1-/- cells re-replicate their DNA and become polyploid. In light of these results, we propose that p21waf1 simultaneously targets cdk and transcriptional regulators to prevent the expression of oncogenic pathways upon DNA damage.
Vigneron
Arnaud
A
INSERM U564, Cancer Center Paul Papin, 49033 Angers, France.
Cherier
Julia
J
Barré
Benjamin
B
Gamelin
Erick
E
Coqueret
Olivier
O
D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D015536:Down-Regulation; D017353:Gene Deletion; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D020687:cdc25 Phosphatases / Q000235:genetics*; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D050880:p300-CBP Transcription Factors; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases