title: Epigenetic Enhancement of the Post-replicative DNA Mismatch Repair of Mammalian Genomes by a Hemi-mCpG-Np95-Dnmt1 Axis.
abstract: DNA methylation at C of CpG dyads (mCpG) in vertebrate genomes is essential for gene regulation, genome stability and development. We show in this study that proper functioning of post-replicative DNA mismatch repair (MMR) in mammalian cells relies on the presence of genomicmCpG, as well as on the maintenance DNA methyltransferase Dnmt1 independently of its catalytic activity. More importantly, high efficiency of mammalian MMR surveillance is achieved through a hemi-mCpG-Np95(Uhrf1)-Dnmt1 axis, in which the MMR surveillance complex(es) is recruited to post-replicative DNA by Dnmt1, requiring its interactions with MutSα, as well as with Np95 bound at the hemi-methylated CpG sites. Thus, efficiency of MMR surveillance over the mammalian genome in vivo is enhanced at the epigenetic level. This synergy endows vertebrate CpG methylation with a new biological significance and, consequently, an additional mechanism for the maintenance of vertebrate genome stability.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan.
authors.forename: Keh-Yang
authors.initials: KY
authors.lastname: Wang
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan.
authors.forename: Chun-Chang
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Genome Research Center, National Yang-Ming University, Taipei 11221, Taiwan.|Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, Taiwan.|Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 35053, Taiwan.
authors.forename: Shih-Feng
authors.initials: SF
authors.lastname: Tsai
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan.
authors.forename: Che-Kun James
authors.initials: CJ
authors.lastname: Shen
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D018899:CpG Islands; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D016678:Genome; D042822:Genomic Instability; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D009687:Nuclear Proteins; D004247:DNA; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse