title: Influence of oxidized purine processing on strand directionality of mismatch repair.
abstract: Replicative DNA polymerases are high fidelity enzymes that misincorporate nucleotides into nascent DNA with a frequency lower than [1/10(5)], and this precision is improved to about [1/10(7)] by their proofreading activity. Because this fidelity is insufficient to replicate most genomes without error, nature evolved postreplicative mismatch repair (MMR), which improves the fidelity of DNA replication by up to 3 orders of magnitude through correcting biosynthetic errors that escaped proofreading. MMR must be able to recognize non-Watson-Crick base pairs and excise the misincorporated nucleotides from the nascent DNA strand, which carries by definition the erroneous genetic information. In eukaryotes, MMR is believed to be directed to the nascent strand by preexisting discontinuities such as gaps between Okazaki fragments in the lagging strand or breaks in the leading strand generated by the mismatch-activated endonuclease of the MutL homologs PMS1 in yeast and PMS2 in vertebrates. We recently demonstrated that the eukaryotic MMR machinery can make use also of strand breaks arising during excision of uracils or ribonucleotides from DNA. We now show that intermediates of MutY homolog-dependent excision of adenines mispaired with 8-oxoguanine (G(O)) also act as MMR initiation sites in extracts of human cells or Xenopus laevis eggs. Unexpectedly, G(O)/C pairs were not processed in these extracts and failed to affect MMR directionality, but extracts supplemented with exogenous 8-oxoguanine DNA glycosylase (OGG1) did so. Because OGG1-mediated excision of G(O) might misdirect MMR to the template strand, our findings suggest that OGG1 activity might be inhibited during MMR.
authors.affiliation: From the Institute of Molecular Cancer Research of the University of Zurich and the Swiss Institutes of Technology Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Repmann
authors.affiliation: From the Institute of Molecular Cancer Research of the University of Zurich and the Swiss Institutes of Technology Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Maite
authors.initials: M
authors.lastname: Olivera-Harris
authors.affiliation: From the Institute of Molecular Cancer Research of the University of Zurich and the Swiss Institutes of Technology Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland jiricny@imcr.uzh.ch.
authors.forename: Josef
authors.initials: J
authors.lastname: Jiricny
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D020137:Base Pair Mismatch; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D008969:Molecular Sequence Data; D000070956:MutL Proteins; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction; D011687:Purines / Q000737:chemistry / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C022262:Okazaki fragments; C088858:PMS1 protein, S cerevisiae; D011687:Purines; D029701:Saccharomyces cerevisiae Proteins; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070956:MutL Proteins; D045643:DNA Repair Enzymes; C030985:purine
keywords: Base Excision Repair (BER); DNA Damage; DNA Mismatch Repair; DNA Repair; Oxidative Stress