title: Structure and function of the mouse DNA methyltransferase gene: Dnmt1 shows a tripartite structure.
abstract: Dnmt1 is the predominant DNA methyltransferase (MTase) in mammals. The C-terminal domain of Dnmt1 clearly shares sequence similarity with many prokaryotic 5mC methyltransferases, and had been proposed to be sufficient for catalytic activity. We show here by deletion analysis that the C-terminal domain alone is not sufficient for methylating activity, but that a large part of the N-terminal domain is required in addition. Since this complex structure of Dnmt1 raises issues about its evolutionary origin, we have compared several eukaryotic MTases and have determined the genomic organization of the mouse Dnmt1 gene. The 5' most part of the N-terminal domain is dispensible for enzyme activity, includes the major nuclear import signal and comprises tissue-specific exons. Interestingly, the functional subdivision of Dnmt1 correlates well with the structure of the Dnmt1 gene in terms of intron/exon size distribution as well as sequence conservation. Our results, based on functional, structural and sequence comparison data, suggest that the gene has evolved from the fusion of at least three genes.
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, D-13125, Germany.
authors.forename: J B
authors.initials: JB
authors.lastname: Margot
authors.forename: A M
authors.initials: AM
authors.lastname: Aguirre-Arteta
authors.forename: B V
authors.initials: BV
authors.lastname: Di Giacco
authors.forename: S
authors.initials: S
authors.lastname: Pradhan
authors.forename: R J
authors.initials: RJ
authors.lastname: Roberts
authors.forename: M C
authors.initials: MC
authors.lastname: Cardoso
authors.forename: H
authors.initials: H
authors.lastname: Leonhardt
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001483:Base Sequence; D002384:Catalysis; D020134:Catalytic Domain / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D019913:Nuclear Localization Signals / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D007527:Isoenzymes; D019913:Nuclear Localization Signals; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse