Replication protein A and proliferating cell nuclear antigen coordinate DNA polymerase selection in 8-oxo-guanine repair

Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20689-94. doi: 10.1073/pnas.0811241106. Epub 2008 Dec 22.

Abstract

The adenine misincorporated by replicative DNA polymerases (pols) opposite 7,8-dihydro-8-oxoguanine (8-oxo-G) is removed by a specific glycosylase, leaving the lesion on the DNA. Subsequent incorporation of C opposite 8-oxo-G on the resulting 1-nt gapped DNA is essential for the removal of the 8-oxo-G to prevent G-C to T-A transversion mutations. By using model DNA templates, purified DNA pols beta and lambda and knockout cell extracts, we show here that the auxiliary proteins replication protein A and proliferating cell nuclear antigen act as molecular switches to activate the DNA pol lambda- dependent highly efficient and faithful repair of A:8-oxo-G mismatches in human cells and to repress DNA pol beta activity. By using an immortalized human fibroblast cell line that has the potential to induce cancer in mice, we show that the development of a tumoral phenotype in these cells correlated with a differential expression of DNA pols lambda and beta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Transformed
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell-Free System / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA / genetics
  • DNA / metabolism
  • DNA Glycosylases / genetics
  • DNA Glycosylases / metabolism
  • DNA Polymerase beta / genetics
  • DNA Polymerase beta / metabolism*
  • DNA Repair* / genetics
  • DNA Replication / genetics
  • Guanine / analogs & derivatives*
  • Guanine / metabolism
  • Humans
  • Mice
  • Mutation
  • Proliferating Cell Nuclear Antigen / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Reactive Oxygen Species / metabolism
  • Replication Protein A / genetics
  • Replication Protein A / metabolism*
  • Tumor Suppressor Protein p14ARF / genetics
  • Tumor Suppressor Protein p14ARF / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • 7,8-dihydro-8-oxoguanine
  • Cyclin-Dependent Kinase Inhibitor p16
  • MYC protein, human
  • Proliferating Cell Nuclear Antigen
  • Proto-Oncogene Proteins c-myc
  • Reactive Oxygen Species
  • Replication Protein A
  • TP53 protein, human
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • Guanine
  • DNA
  • DNA Polymerase beta
  • DNA polymerase beta2
  • DNA Glycosylases
  • mutY adenine glycosylase