Replication protein A and proliferating cell nuclear antigen coordinate DNA polymerase selection in 8-oxo-guanine repair |
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| Authors: | Giovanni Maga, Emmanuele Crespan, Ursula Wimmer, Barbara van Loon, Alessandra Amoroso, Chiara Mondello, Cristina Belgiovine, Elena Ferrari, Giada Locatelli, Giuseppe Villani, Ulrich Hü bscher |
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| Affiliation: | Giovanni Maga, Emmanuele Crespan, Ursula Wimmer, Barbara van Loon, Alessandra Amoroso, Chiara Mondello, Cristina Belgiovine, Elena Ferrari, Giada Locatelli, Giuseppe Villani, and Ulrich Hübscher |
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| 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 β and λ 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 λ- dependent highly efficient and faithful repair of A:8-oxo-G mismatches in human cells and to repress DNA pol β 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 λ and β. |
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