UHRF1, a modular multi-domain protein, regulates replication-coupled crosstalk between DNA methylation and histone modifications

Hideharu Hashimoto; John R. Horton; Xing Zhang; Xiaodong Cheng

doi:10.4161/epi.4.1.7370

UHRF1, a modular multi-domain protein, regulates replication-coupled crosstalk between DNA methylation and histone modifications

Hideharu Hashimoto, John R. Horton, Xing Zhang, Xiaodong Cheng

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

104 Scopus citations

Abstract

Cytosine methylation in DNA is a major epigenetic signal, and plays a central role in propagating chromatin status during cell division. However the mechanistic links between DNA methylation and histone methylation are poorly understood. A multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is required for DNA CpG maintenance methylation at replication forks, and mouse UHRF1-null cells show enhanced susceptibility to DNA replication arrest and DNA damaging agents. Recent data demonstrated that the SET and RING associated (SRA) domain of UHRF1 binds hemimethylated CpG and flips 5-methylcytosine out of the DNA helix, whereas its tandom tudor domain and PHD domain bind the tail of histone H3 in a highly methylation sensitive manner. We hypothesize that UHRF1 brings the two components (histones and DNA) carrying appropriate markers (on the tails of H3 and hemimethylated CpG sites) ready to be assembled into a nucleosome after replication.

Original language	English (US)
Pages (from-to)	8-14
Number of pages	7
Journal	Epigenetics
Volume	4
Issue number	1
DOIs	https://doi.org/10.4161/epi.4.1.7370
State	Published - 2009
Externally published	Yes

Keywords

Base flipping
DNA methylation
Histone modifications
Inter-domain interactions
SRA domain

ASJC Scopus subject areas

Molecular Biology
Cancer Research

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10.4161/epi.4.1.7370

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title = "UHRF1, a modular multi-domain protein, regulates replication-coupled crosstalk between DNA methylation and histone modifications",

abstract = "Cytosine methylation in DNA is a major epigenetic signal, and plays a central role in propagating chromatin status during cell division. However the mechanistic links between DNA methylation and histone methylation are poorly understood. A multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is required for DNA CpG maintenance methylation at replication forks, and mouse UHRF1-null cells show enhanced susceptibility to DNA replication arrest and DNA damaging agents. Recent data demonstrated that the SET and RING associated (SRA) domain of UHRF1 binds hemimethylated CpG and flips 5-methylcytosine out of the DNA helix, whereas its tandom tudor domain and PHD domain bind the tail of histone H3 in a highly methylation sensitive manner. We hypothesize that UHRF1 brings the two components (histones and DNA) carrying appropriate markers (on the tails of H3 and hemimethylated CpG sites) ready to be assembled into a nucleosome after replication.",

keywords = "Base flipping, DNA methylation, Histone modifications, Inter-domain interactions, SRA domain",

author = "Hideharu Hashimoto and Horton, {John R.} and Xing Zhang and Xiaodong Cheng",

note = "Funding Information: We thank Dr. Ashok Bhagwat for critical comments. The Emory University School of Medicine supported the use of SER-CAT beam-lines. This work was supported by grant GM049245 to X.C. from the National Institutes of Health (NIH). X.C. is a Georgia Research Alliance Eminent Scholar. The X-ray structures (coordinates and structure factor files) of mouse UHRF1 SRA with bound DNA have been submitted to PDB as 3FDE (crystal form 1), 3F8J (crystal form 2) and 3F8I (crystal from 3) respectively. Correspondence and requests for materials should be addressed to xcheng@emory.edu.",

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N1 - Funding Information: We thank Dr. Ashok Bhagwat for critical comments. The Emory University School of Medicine supported the use of SER-CAT beam-lines. This work was supported by grant GM049245 to X.C. from the National Institutes of Health (NIH). X.C. is a Georgia Research Alliance Eminent Scholar. The X-ray structures (coordinates and structure factor files) of mouse UHRF1 SRA with bound DNA have been submitted to PDB as 3FDE (crystal form 1), 3F8J (crystal form 2) and 3F8I (crystal from 3) respectively. Correspondence and requests for materials should be addressed to xcheng@emory.edu.

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N2 - Cytosine methylation in DNA is a major epigenetic signal, and plays a central role in propagating chromatin status during cell division. However the mechanistic links between DNA methylation and histone methylation are poorly understood. A multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is required for DNA CpG maintenance methylation at replication forks, and mouse UHRF1-null cells show enhanced susceptibility to DNA replication arrest and DNA damaging agents. Recent data demonstrated that the SET and RING associated (SRA) domain of UHRF1 binds hemimethylated CpG and flips 5-methylcytosine out of the DNA helix, whereas its tandom tudor domain and PHD domain bind the tail of histone H3 in a highly methylation sensitive manner. We hypothesize that UHRF1 brings the two components (histones and DNA) carrying appropriate markers (on the tails of H3 and hemimethylated CpG sites) ready to be assembled into a nucleosome after replication.

AB - Cytosine methylation in DNA is a major epigenetic signal, and plays a central role in propagating chromatin status during cell division. However the mechanistic links between DNA methylation and histone methylation are poorly understood. A multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is required for DNA CpG maintenance methylation at replication forks, and mouse UHRF1-null cells show enhanced susceptibility to DNA replication arrest and DNA damaging agents. Recent data demonstrated that the SET and RING associated (SRA) domain of UHRF1 binds hemimethylated CpG and flips 5-methylcytosine out of the DNA helix, whereas its tandom tudor domain and PHD domain bind the tail of histone H3 in a highly methylation sensitive manner. We hypothesize that UHRF1 brings the two components (histones and DNA) carrying appropriate markers (on the tails of H3 and hemimethylated CpG sites) ready to be assembled into a nucleosome after replication.

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UHRF1, a modular multi-domain protein, regulates replication-coupled crosstalk between DNA methylation and histone modifications

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Keywords

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