title: Methylation of histone H3 on lysine 79 associates with a group of replication origins and helps limit DNA replication once per cell cycle.
abstract: Mammalian DNA replication starts at distinct chromosomal sites in a tissue-specific pattern coordinated with transcription, but previous studies have not yet identified a chromatin modification that correlates with the initiation of DNA replication at particular genomic locations. Here we report that a distinct fraction of replication initiation sites in the human genome are associated with a high frequency of dimethylation of histone H3 lysine K79 (H3K79Me2). H3K79Me2-containing chromatin exhibited the highest genome-wide enrichment for replication initiation events observed for any chromatin modification examined thus far (23.39% of H3K79Me2 peaks were detected in regions adjacent to replication initiation events). The association of H3K79Me2 with replication initiation sites was independent and not synergistic with other chromatin modifications. H3K79 dimethylation exhibited wider distribution on chromatin during S-phase, but only regions with H3K79 methylation in G1 and G2 were enriched in replication initiation events. H3K79 was dimethylated in a region containing a functional replicator (a DNA sequence capable of initiating DNA replication), but the methylation was not evident in a mutant replicator that could not initiate replication. Depletion of DOT1L, the sole enzyme responsible for H3K79 methylation, triggered limited genomic over-replication although most cells could continue to proliferate and replicate DNA in the absence of methylated H3K79. Thus, prevention of H3K79 methylation might affect regulatory processes that modulate the order and timing of DNA replication. These data are consistent with the hypothesis that dimethylated H3K79 associates with some replication origins and marks replicated chromatin during S-phase to prevent re-replication and preserve genomic stability.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Fu
authors.forename: Alika K
authors.initials: AK
authors.lastname: Maunakea
authors.forename: Melvenia M
authors.initials: MM
authors.lastname: Martin
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Ryan
authors.forename: RyangGuk
authors.initials: R
authors.lastname: Kim
authors.forename: Chii Meil
authors.initials: CM
authors.lastname: Lin
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.forename: Mirit I
authors.initials: MI
authors.lastname: Aladjem
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D002843:Chromatin / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D015894:Genome, Human; D042822:Genomic Instability; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000235:genetics*; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics; D018741:Replication Origin / Q000235:genetics; D016196:S Phase / Q000235:genetics
chemical_list: D002843:Chromatin; D006657:Histones; D056466:Histone Demethylases; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase