Implication of p53 in base excision DNA repair: in vivo evidence.
The tumor suppressor p53 plays an important role in response to DNA damage, including DNA repair. One DNA repair pathway, nucleotide excision repair (NER), has been well-documented to be regulated by p53. It seemed probable that p53 may affect other DNA repair pathways. We employed matched isogenic pairs of cell lines, wild-type or p53-deficient, to investigate this question using methyl methanesulfonate (MMS), a base-damaging agent. Alkylation damage induced by MMS is repaired exclusively by the base excision repair (BER) pathway. Cells carrying mutant or no p53 genes exhibited slow BER of MMS-induced DNA damage, and exhibited MMS-sensitivity. One contributing factor is the abundance of DNA polymerase beta (beta-pol), an enzyme required for BER, which was almost absent in p53 mutant and p53-null cells. Our findings demonstrate an in vivo requirement for p53 in regulating the base excision repair response, a novel finding of great potential importance in understanding the DNA repair branch of the p53 pathway.
Seo
Young R
YR
Indiana University Cancer Center, Department of Microbiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Fishel
Melissa L
ML
Amundson
Sally
S
Kelley
Mark R
MR
Smith
Martin L
ML
D000818:Animals; D017209:Apoptosis; D019757:Carbon-Oxygen Lyases / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D020552:Comet Assay; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D006801:Humans; D007700:Kinetics; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D051379:Mice; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D009153:Mutagens; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D008741:Methyl Methanesulfonate; D019951:DNA Polymerase beta; D019757:Carbon-Oxygen Lyases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase