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

Giovanni Maga; Emmanuele Crespan; Ursula Wimmer; Barbara van Loon; Alessandra Amoroso; Chiara Mondello; Cristina Belgiovine; Elena Ferrari; Giada Locatelli; Giuseppe Villani; Ulrich Hübscher

doi:10.1073/pnas.0811241106

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.

Authors

Giovanni Maga¹, Emmanuele Crespan, Ursula Wimmer, Barbara van Loon, Alessandra Amoroso, Chiara Mondello, Cristina Belgiovine, Elena Ferrari, Giada Locatelli, Giuseppe Villani, Ulrich Hübscher

Affiliation

¹ Institute of Molecular Genetics, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, I-27100 Pavia, Italy. maga@igm.cnr.it

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 beta2
DNA Polymerase beta
DNA Glycosylases
mutY adenine glycosylase