RPA and ATR link transcriptional stress to p53

Frederick A. Derheimer, Heather O'Hagan, Heather M. Krueger, Sheela Hanasoge, Michelle T. Paulsen, Mats Ljungman

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

The mechanisms by which DNA-damaging agents trigger the induction of the stress response protein p53 are poorly understood but may involve alterations of chromatin structure or blockage of either transcription or replication. Here we show that transcription-blocking agents can induce phosphorylation of the Ser-15 site of p53 in a replication-independent manner. Furthermore, microinjection of anti-RNA polymerase II antibodies into the nuclei of cells showed that blockage of transcription is sufficient for p53 accumulation even in the absence of DNA damage. This induction of p53 occurs by two independent mechanisms. First, accumulation of p53 is linked to diminished nuclear export of mRNA; and second, inhibition specifically of elongating RNA polymerase II complexes results in the phosphorylation of the Ser-15 site of p53 in a replication protein A (RPA)- and ATM and Rad3-related (ATR)-dependent manner. We propose that this transcription-based stress response involving RPA, ATR, and p53 has evolved as a DNA damage-sensing mechanism to safeguard cells against DNA damage-induced mutagenesis.

Original languageEnglish (US)
Pages (from-to)12778-12783
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number31
DOIs
StatePublished - Jul 31 2007
Externally publishedYes

Fingerprint

Replication Protein A
DNA Damage
RNA Polymerase II
Phosphorylation
Cell Nucleus Active Transport
Microinjections
Heat-Shock Proteins
Cell Nucleus
Mutagenesis
Chromatin
Messenger RNA
Antibodies
DNA

Keywords

  • Antibody microinjection
  • DNA damage response
  • Nuclear export
  • Phosphorylation
  • RNA polymerase II

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

RPA and ATR link transcriptional stress to p53. / Derheimer, Frederick A.; O'Hagan, Heather; Krueger, Heather M.; Hanasoge, Sheela; Paulsen, Michelle T.; Ljungman, Mats.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 31, 31.07.2007, p. 12778-12783.

Research output: Contribution to journalArticle

Derheimer, Frederick A. ; O'Hagan, Heather ; Krueger, Heather M. ; Hanasoge, Sheela ; Paulsen, Michelle T. ; Ljungman, Mats. / RPA and ATR link transcriptional stress to p53. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 31. pp. 12778-12783.
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