title: HhaI and HpaII DNA methyltransferases bind DNA mismatches, methylate uracil and block DNA repair.
abstract: The hydrolytic deamination of 5-methylcytosine (5-mC) to thymine (T) is believed to be responsible for the high mutability of the CpG dinucleotide in DNA. We have shown a possible alternate mechanism for mutagenesis at CpG in which HpaII DNA-(cytosine-5) methyltransferase (M.HpaII) can enzymatically deaminate cytosine (C) to uracil (U) in DNA [Shen, J.-C., Rideout, W.M., III and Jones, P.A., Cell, 71, 1073-1080, (1992)]. Both the hydrolytic deamination of 5-mC and enzymatic deamination of C create premutagenic DNA mismatches (G:U and G:T) with the guanine (G) originally paired to the normal C. Surprisingly, we found that DNA-(cytosine-5) methyltransferases have higher affinities for these DNA mismatches than for their normal G:C targets and are capable of transferring a methyl group to the 5-position of U, creating T at low efficiencies. This binding by methyltransferase to mismatches at the recognition site prevented repair of G:U mismatches by uracil DNA glycosylase in vitro.
authors.affiliation: Department of Biochemistry and Molecular Biology, Kenneth Norris Jr Comprehensive Cancer Center, University of Southern California School of Medicine, Los Angeles 90033, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Yang
authors.forename: J C
authors.initials: JC
authors.lastname: Shen
authors.forename: J M
authors.initials: JM
authors.lastname: Zingg
authors.forename: S
authors.initials: S
authors.lastname: Mi
authors.forename: P A
authors.initials: PA
authors.lastname: Jones
mesh_terms: D001483:Base Sequence; D003596:Cytosine / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D045647:DNA Glycosylases; D004260:DNA Repair / Q000502:physiology*; D015257:DNA-Cytosine Methylases / Q000378:metabolism*; D003641:Deamination; D015226:Dinucleoside Phosphates / Q000378:metabolism; D007700:Kinetics; D008745:Methylation; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D009692:Nucleic Acid Heteroduplexes / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism; D013379:Substrate Specificity; D014498:Uracil / Q000378:metabolism*; D051981:Uracil-DNA Glycosidase
chemical_list: D003596:Cytosine; D004247:DNA; D045647:DNA Glycosylases; D015257:DNA-Cytosine Methylases; D015226:Dinucleoside Phosphates; D009699:N-Glycosyl Hydrolases; D009692:Nucleic Acid Heteroduplexes; D012436:S-Adenosylmethionine; D014498:Uracil; D051981:Uracil-DNA Glycosidase; C015772:CpG dinucleotide; C037664:DNA modification methylase HhaI; C029641:DNA modification methylase HpaII