Effect of 8-oxoguanine and abasic site DNA lesions on <i>in vitro</i> elongation by human DNA polymerase ϵ in the presence of replication protein A and proliferating-cell nuclear antigen

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  • Giada A. Locatelli
    Institut de Pharmacologie et de Biologie Structurale, CNRS-Université Paul Sabatier Toulouse III, UMR 5089, 205 Route de Narbonne, 31077 Toulouse cedex, France
  • Helmut Pospiech
    Leibniz Institute for Age Research – Fritz Lipman Institute, Beutenbergstrasse 11, D-07745 Jena, Germany
  • Nicolas Tanguy Le Gac
    Institut de Pharmacologie et de Biologie Structurale, CNRS-Université Paul Sabatier Toulouse III, UMR 5089, 205 Route de Narbonne, 31077 Toulouse cedex, France
  • Barbara van Loon
    Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich-Irchel, CH-8057, Zürich, Switzerland
  • Ulrich Hubscher
    Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich-Irchel, CH-8057, Zürich, Switzerland
  • Sinikka Parkkinen
    Department of Biology, University of Eastern Finland, P.O. Box 111, FI-80101 Joensuu, Finland
  • Juhani E. Syväoja
    Department of Biology, University of Eastern Finland, P.O. Box 111, FI-80101 Joensuu, Finland
  • Giuseppe Villani
    Institut de Pharmacologie et de Biologie Structurale, CNRS-Université Paul Sabatier Toulouse III, UMR 5089, 205 Route de Narbonne, 31077 Toulouse cedex, France

書誌事項

公開日
2010-07-14
DOI
  • 10.1042/bj20100405
公開者
Portland Press Ltd.

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<jats:p>DNA pol (polymerase) ϵ is thought to be the leading strand replicase in eukaryotes. In the present paper, we show that human DNA pol ϵ can efficiently bypass an 8-oxo-G (7,8-dihydro-8-oxoguanine) lesion on the template strand by inserting either dCMP or dAMP opposite to it, but it cannot bypass an abasic site. During replication, DNA pols associate with accessory proteins that may alter their bypass ability. We investigated the role of the human DNA sliding clamp PCNA (proliferating-cell nuclear antigen) and of the human single-stranded DNA-binding protein RPA (replication protein A) in the modulation of the DNA synthesis and translesion capacity of DNA pol ϵ. RPA inhibited the elongation by human DNA pol ϵ on templates annealed to short primers. PCNA did not influence the elongation by DNA pol ϵ and had no effect on inhibition of elongation caused by RPA. RPA inhibition was considerably reduced when the length of the primers was increased. On templates bearing the 8-oxo-G lesion, this inhibitory effect was more pronounced on DNA replication beyond the lesion, suggesting that RPA may prevent extension by DNA pol ϵ after incorporation opposite an 8-oxo-G. Neither PCNA nor RPA had any effect on the inability of DNA pol ϵ to replicate past the AP site, independent of the primer length.</jats:p>

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