Induction of ser15 and lys382 modifications of p53 by blockage of transcription elongation.
Blockage of transcription has been shown to induce the tumor suppressor p53 in human cells. We here show that RNA synthesis inhibitors blocking the phosphorylation of the carboxyl terminal domain (CTD) of RNA polymerase II, such as DRB and H7, induced rapid nuclear accumulation of p53 proteins that were not phosphorylated at ser15 or acetylated at lys382. In contrast, agents that inhibit the elongation phase of transcription, such as UV light, camptothecin or actinomycin D, induced the accumulation of nuclear p53 proteins that were modified at both of these sites. Furthermore, using a panel of DNA repair-deficient cells we show that persistent DNA lesions in the transcribed strand of active genes are responsible for the induction of the ser15 and lys382 modifications following UV-irradiation. We conclude that inhibition of transcription is sufficient for the accumulation of p53 in the nucleus regardless of whether the ser15 site of p53 is phosphorylated or not. Importantly, blockage of the elongation phase of transcription triggers a distinct signaling pathway leading to p53 modifications on ser15 and lys382. We propose that the elongating RNA polymerase complex may act as a sensor of DNA damage and as an integrator of cellular stress signals.
Ljungman
M
M
Department of Radiation Oncology, Division of Cancer Biology, University of Michigan Comprehensive Cancer Center, 150 E. Medical Center Drive, Ann Arbor, MI 48109-0936, USA. ljungman@umich.edu
O'Hagan
H M
HM
Paulsen
M T
MT
D000107:Acetylation; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003057:Cockayne Syndrome / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000502:physiology; D012694:Serine / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism
D019384:Nucleic Acid Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D012694:Serine; D012319:RNA Polymerase II; D008239:Lysine