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Review
. 2016 Jan;159(1):9-15.
doi: 10.1093/jb/mvv113. Epub 2015 Nov 20.

Regulation of maintenance DNA methylation via histone ubiquitylation

Atsuya Nishiyama  1 , Luna Yamaguchi  1 , Makoto Nakanishi  2
Affiliations
Review

Regulation of maintenance DNA methylation via histone ubiquitylation

Atsuya Nishiyama et al. J Biochem. 2016 Jan.

Abstract

DNA methylation is one of the most stable but dynamically regulated epigenetic marks that act as determinants of cell fates during embryonic development through regulation of various forms of gene expression. DNA methylation patterns must be faithfully propagated throughout successive cell divisions in order to maintain cell-specific function. We have recently demonstrated that Uhrf1-dependent ubiquitylation of histone H3 at lysine 23 is critical for Dnmt1 recruitment to DNA replication sites, which catalyzes the conversion of hemi-methylated DNA to fully methylated DNA. In this review, we provide an overview of recent progress in understanding the mechanism underlying maintenance DNA methylation.

Keywords: DNA methylation; DNA methyltransferase 1, histone; Ubiquitin; cell cycle.

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Figures

Fig. 1
Fig. 1
DNA replication and Uhrf1-dependent chromatin loading of Dnmt1 in Xenopus egg extracts. Schematic representation of Geminin and p27 functions in DNA replication. ORC: origin recognition complex, Pre-RC: pre-replication complex, MCM: minichromosome maintenance (upper panel). Meiotic metaphase II (MII) arrested cytostatic factor (CSF) extracts were incubated with demembraned Xenopus sperm (XSP) nuclei to assemble mitotic chromatin for 30 min. The extracts arrested in MII were released into interphase by addition of CaCl2, leading to degradation of mitotic cyclins by the APC/C, exit from mitosis and initiation of DNA replication (middle panel). Loading of Dnmt1 and Uhrf1 is dependent on DNA replication. DMSO (Control), Geminin or GST-p27 were added to the activated CSF extracts for inhibition of DNA replication. Sperm chromatin fractions at the indicated times and mitotic chromatin (-Ca2+) were analyzed by immunoblotting (IB) H3 Ser10-P: phosphorylation of H3 at Ser 10, a marker of mitosis (lower panels).
Fig. 2
Fig. 2
Uhrf1 plays an essential role in the recruitment of Dnmt1 to hemi-methylated DNA regions during DNA replication. (A) Methylated cytosine cannot be replicated by DNA replication machinery, generating hemi-methylated DNA. Uhrf1 could specifically bind to hemi-methylated DNA. Uhrf1 then recruits Dnmt1 around the sites of hemi-methylated DNA although molecular mechanism underlying this recruitment remains to be elusive. The recruited Dnmt1 then catalyzes the conversion of himi-metylated DNA to full methylated DNA. (B) Uhrf1 contains various unique domains. TUDOR and PHD domains function as a single unit for readout of H3K9 methylation. SRA domain is a hemi-methylated DNA binding domain, flipping 5-methylcytosine out of the DNA helix. The carboxyl-terminal RING finger domain ubiquitylates H3K23 in a DNA replication-dependent manner. The amino-terminal ubiquitin like domain (UBQ) presents a highest homology with ubiquitin molecule, but its function remains elusive.
Fig. 3
Fig. 3
A proposed model of the regulation of maintenance DNA methylation through Uhrf1-mediated H3K23 and/or H3K18 ubiquitylations. After DNA replication, existing fully methylated DNA cannot be replicated by a canonical DNA replication system, generating hemi-methylated DNA. Uhrf1 specifically binds to hemi-methylated DNA and ubiquitylates H3K23 and/or H3K18. Ubiquitylations of H3K23 and/or H3K18 specifically recruit Dnmt1 at the sites of DNA replication. The recruited Dnmt1 then catalyzes the conversion of hemi-methylated DNA to fully methylated DNA.
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