title: Loss of maintenance DNA methylation results in abnormal DNA origin firing during DNA replication.
abstract: The mammalian maintenance methyltransferase DNMT1 [DNA (cytosine-5-)-methyltransferase 1] mediates the inheritance of the DNA methylation pattern during replication. Previous studies have shown that depletion of DNMT1 causes a severe growth defect and apoptosis in differentiated cells. However, the detailed mechanisms behind this phenomenon remain poorly understood. Here we show that conditional ablation of Dnmt1 in murine embryonic fibroblasts (MEFs) resulted in an aberrant DNA replication program showing an accumulation of late-S phase replication and causing severely defective growth. Furthermore, we found that the catalytic activity and replication focus targeting sequence of DNMT1 are required for a proper DNA replication program. Taken together, our findings suggest that the maintenance of DNA methylation by DNMT1 plays a critical role in proper regulation of DNA replication in mammalian cells.
authors.affiliation: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Haruta
authors.affiliation: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Electronic address: midorism@med.nagoya-cu.ac.jp.
authors.forename: Midori
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Atsuya
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Johmura
authors.affiliation: Institut Curie, Centre de Recherche, 26 rue d'Ulm, CNRS UMR 3244, 75248 ParisCedex 05, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Le Tallec
authors.affiliation: Institut Curie, Centre de Recherche, 26 rue d'Ulm, CNRS UMR 3244, 75248 ParisCedex 05, France.
authors.forename: Michelle
authors.initials: M
authors.lastname: Debatisse
authors.affiliation: Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Electronic address: mkt-naka@med.nagoya-cu.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakanishi
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D005347:Fibroblasts / Q000502:physiology; D018816:Genes, cdc / Q000235:genetics; D051379:Mice; D064110:Minichromosome Maintenance Proteins / Q000235:genetics*; D018741:Replication Origin / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: C411744:DMAP1 protein, human; D012097:Repressor Proteins; D064110:Minichromosome Maintenance Proteins
keywords: DNA methylation; DNA replication; DNMT1