A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks

Hongda Huang; Caroline B. Strømme; Giulia Saredi; Martina Hödl; Anne Strandsby; Cristina González-Aguilera; Shoudeng Chen; Anja Groth; Dinshaw J Patel

doi:10.1038/nsmb.3055

A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks

Hongda Huang, Caroline B. Strømme, Giulia Saredi, Martina Hödl, Anne Strandsby, Cristina González-Aguilera, Shoudeng Chen, Anja Groth, Dinshaw J Patel

104 Citations (Scopus)

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.

Original language	English
Journal	Nature Structural and Molecular Biology
Volume	22
Issue number	8
Pages (from-to)	618-626
Number of pages	9
ISSN	1545-9993
DOIs	https://doi.org/10.1038/nsmb.3055
Publication status	Published - 7 Aug 2015

Keywords

Amino Acid Sequence
Blotting, Western
Cell Line, Tumor
Chromatin
DNA
DNA Replication
HeLa Cells
Histones
Humans
Minichromosome Maintenance Complex Component 2
Models, Molecular
Molecular Chaperones
Molecular Sequence Data
Mutation
Nucleic Acid Conformation
Protein Binding
Protein Multimerization
Protein Structure, Tertiary
RNA Interference
Sequence Homology, Amino Acid
Journal Article
Research Support, Non-U.S. Gov't

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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.",

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author = "Hongda Huang and Str{\o}mme, {Caroline B.} and Giulia Saredi and Martina H{\"o}dl and Anne Strandsby and Cristina Gonz{\'a}lez-Aguilera and Shoudeng Chen and Anja Groth and Patel, {Dinshaw J}",

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AU - Huang, Hongda

AU - Strømme, Caroline B.

AU - Saredi, Giulia

AU - Hödl, Martina

AU - Strandsby, Anne

AU - González-Aguilera, Cristina

AU - Chen, Shoudeng

AU - Groth, Anja

AU - Patel, Dinshaw J

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N2 - 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.

AB - 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.

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KW - Minichromosome Maintenance Complex Component 2

KW - Models, Molecular

KW - Molecular Chaperones

KW - Molecular Sequence Data

KW - Mutation

KW - Nucleic Acid Conformation

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KW - Protein Multimerization

KW - Protein Structure, Tertiary

KW - RNA Interference

KW - Sequence Homology, Amino Acid

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JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

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ER -

A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks

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Keywords

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