The Mcm2-Ctf4-Polα Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands

Haiyun Gan; Albert Serra-Cardona; Xu Hua; Hui Zhou; Karim Labib; Chuanhe Yu; Zhiguo Zhang

doi:10.1016/j.molcel.2018.09.001

The Mcm2-Ctf4-Polα Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands

Haiyun Gan, Albert Serra-Cardona, Xu Hua, Hui Zhou, Karim Labib, Chuanhe Yu, Zhiguo Zhang

Research output: Contribution to journal › Article › peer-review

104 Scopus citations

Abstract

Although essential for epigenetic inheritance, the transfer of parental histone (H3-H4)₂ tetramers that contain epigenetic modifications to replicating DNA strands is poorly understood. Here, we show that the Mcm2-Ctf4-Polα axis facilitates the transfer of parental (H3-H4)₂ tetramers to lagging-strand DNA at replication forks. Mutating the conserved histone-binding domain of the Mcm2 subunit of the CMG (Cdc45-MCM-GINS) DNA helicase, which translocates along the leading-strand template, results in a marked enrichment of parental (H3-H4)₂ on leading strand, due to the impairment of the transfer of parental (H3-H4)₂ to lagging strands. Similar effects are observed in Ctf4 and Polα primase mutants that disrupt the connection of the CMG helicase to Polα that resides on lagging-strand template. Our results support a model whereby parental (H3-H4)₂ complexes displaced from nucleosomes by DNA unwinding at replication forks are transferred by the CMG-Ctf4-Polα complex to lagging-strand DNA for nucleosome assembly at the original location. How parental histone H3-H4 tetramers are transferred to replicating DNA strands for epigenetic inheritance remains largely unknown. Gan et al. show that parental H3-H4 tetramers bind to Mcm2, which travels along the leading-strand template, and are then transferred to the lagging strand by the Mcm2-Ctf4-Polα complex for nucleosome assembly.

Original language	English (US)
Pages (from-to)	140-151.e3
Journal	Molecular Cell
Volume	72
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2018.09.001
State	Published - Oct 4 2018
Externally published	Yes

Bibliographical note

Funding Information:
We thank Dr. Richard Baer and Rebecca Burgess for editing and comments on this manuscript, Dr. Sontao Jia for discussion, and Dr. Jasper Rine for yeast strains. This study was supported by NIH grant ( R35GM118015 to Z.Z.), the MRC ( MC_UU_12016/13 to K.L.), and the Wellcome Trust (reference 102943/Z/13/Z to K.L.).

Funding Information:
We thank Dr. Richard Baer and Rebecca Burgess for editing and comments on this manuscript, Dr. Sontao Jia for discussion, and Dr. Jasper Rine for yeast strains. This study was supported by NIH grant (R35GM118015 to Z.Z.), the MRC (MC_UU_12016/13 to K.L.), and the Wellcome Trust (reference 102943/Z/13/Z to K.L.).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

Ctf4
DNA replication
Mcm2
Pol1
epigenetic inheritance
histone modifications
nucleosome assembly
parental histone transfer

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abstract = "Although essential for epigenetic inheritance, the transfer of parental histone (H3-H4)2 tetramers that contain epigenetic modifications to replicating DNA strands is poorly understood. Here, we show that the Mcm2-Ctf4-Polα axis facilitates the transfer of parental (H3-H4)2 tetramers to lagging-strand DNA at replication forks. Mutating the conserved histone-binding domain of the Mcm2 subunit of the CMG (Cdc45-MCM-GINS) DNA helicase, which translocates along the leading-strand template, results in a marked enrichment of parental (H3-H4)2 on leading strand, due to the impairment of the transfer of parental (H3-H4)2 to lagging strands. Similar effects are observed in Ctf4 and Polα primase mutants that disrupt the connection of the CMG helicase to Polα that resides on lagging-strand template. Our results support a model whereby parental (H3-H4)2 complexes displaced from nucleosomes by DNA unwinding at replication forks are transferred by the CMG-Ctf4-Polα complex to lagging-strand DNA for nucleosome assembly at the original location. How parental histone H3-H4 tetramers are transferred to replicating DNA strands for epigenetic inheritance remains largely unknown. Gan et al. show that parental H3-H4 tetramers bind to Mcm2, which travels along the leading-strand template, and are then transferred to the lagging strand by the Mcm2-Ctf4-Polα complex for nucleosome assembly.",

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AU - Zhou, Hui

AU - Labib, Karim

AU - Yu, Chuanhe

AU - Zhang, Zhiguo

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AB - Although essential for epigenetic inheritance, the transfer of parental histone (H3-H4)2 tetramers that contain epigenetic modifications to replicating DNA strands is poorly understood. Here, we show that the Mcm2-Ctf4-Polα axis facilitates the transfer of parental (H3-H4)2 tetramers to lagging-strand DNA at replication forks. Mutating the conserved histone-binding domain of the Mcm2 subunit of the CMG (Cdc45-MCM-GINS) DNA helicase, which translocates along the leading-strand template, results in a marked enrichment of parental (H3-H4)2 on leading strand, due to the impairment of the transfer of parental (H3-H4)2 to lagging strands. Similar effects are observed in Ctf4 and Polα primase mutants that disrupt the connection of the CMG helicase to Polα that resides on lagging-strand template. Our results support a model whereby parental (H3-H4)2 complexes displaced from nucleosomes by DNA unwinding at replication forks are transferred by the CMG-Ctf4-Polα complex to lagging-strand DNA for nucleosome assembly at the original location. How parental histone H3-H4 tetramers are transferred to replicating DNA strands for epigenetic inheritance remains largely unknown. Gan et al. show that parental H3-H4 tetramers bind to Mcm2, which travels along the leading-strand template, and are then transferred to the lagging strand by the Mcm2-Ctf4-Polα complex for nucleosome assembly.

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The Mcm2-Ctf4-Polα Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands

Abstract

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Keywords

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