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

TY - JOUR

T1 - A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks

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

PY - 2015/8/7

Y1 - 2015/8/7

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.

KW - Amino Acid Sequence

KW - Blotting, Western

KW - Cell Line, Tumor

KW - Chromatin

KW - DNA

KW - DNA Replication

KW - HeLa Cells

KW - Histones

KW - Humans

KW - Minichromosome Maintenance Complex Component 2

KW - Models, Molecular

KW - Molecular Chaperones

KW - Molecular Sequence Data

KW - Mutation

KW - Nucleic Acid Conformation

KW - Protein Binding

KW - Protein Multimerization

KW - Protein Structure, Tertiary

KW - RNA Interference

KW - Sequence Homology, Amino Acid

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/nsmb.3055

DO - 10.1038/nsmb.3055

M3 - Journal article

C2 - 26167883

SN - 1545-9993

VL - 22

SP - 618

EP - 626

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 8

ER -