title: A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks.
abstract: During DNA replication, chromatin is reassembled by recycling of modified old histones and deposition of new ones. How histone dynamics integrates with DNA replication to maintain genome and epigenome information remains unclear. Here, we reveal how human MCM2, part of the replicative helicase, chaperones histones H3-H4. Our first structure shows an H3-H4 tetramer bound by two MCM2 histone-binding domains (HBDs), which hijack interaction sites used by nucleosomal DNA. Our second structure reveals MCM2 and ASF1 cochaperoning an H3-H4 dimer. Mutational analyses show that the MCM2 HBD is required for MCM2-7 histone-chaperone function and normal cell proliferation. Further, we show that MCM2 can chaperone both new and old canonical histones H3-H4 as well as H3.3 and CENPA variants. The unique histone-binding mode of MCM2 thus endows the replicative helicase with ideal properties for recycling histones genome wide during DNA replication.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Hongda
authors.initials: H
authors.lastname: Huang
authors.affiliation: Biotech Research and Innovation Centre (BRIC) Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Caroline B
authors.initials: CB
authors.lastname: Strømme
authors.affiliation: Biotech Research and Innovation Centre (BRIC) Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Giulia
authors.initials: G
authors.lastname: Saredi
authors.affiliation: Biotech Research and Innovation Centre (BRIC) Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Martina
authors.initials: M
authors.lastname: Hödl
authors.affiliation: Biotech Research and Innovation Centre (BRIC) Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Strandsby
authors.affiliation: Biotech Research and Innovation Centre (BRIC) Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Cristina
authors.initials: C
authors.lastname: González-Aguilera
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Shoudeng
authors.initials: S
authors.lastname: Chen
authors.affiliation: Biotech Research and Innovation Centre (BRIC) Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anja
authors.initials: A
authors.lastname: Groth
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D064111:Minichromosome Maintenance Complex Component 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid
chemical_list: D002843:Chromatin; D006657:Histones; D018832:Molecular Chaperones; D004247:DNA; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2