The DNA Methyltransferase Dnmt1 Directly Interacts with the SET and RING Finger-associated (SRA) Domain of the Multifunctional Protein Uhrf1 to Facilitate Accession of the Catalytic Center to Hemi-methylated DNA

Berkyurek, Ahmet C.; Suetake, Isao; Arita, Kyohei; Takeshita, Keizo; Nakagawa, Atsushi; Shirakawa, Masahiro; Tsuji, Shoji

doi:10.1074/jbc.m113.523209

Cited by 110 publications

(105 citation statements)

References 23 publications

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“…Addendum-After submission of this article, a study by Berkyurek et al (55) appeared in press, reporting the stimulation of a DNMT1(291-1620) fragment by the UHRF1 SRA domain, which is in agreement with our results.…”

Section: Acknowledgment-the Dnmt1(731-1602) Construct and The Correspsupporting

confidence: 82%

The UHRF1 Protein Stimulates the Activity and Specificity of the Maintenance DNA Methyltransferase DNMT1 by an Allosteric Mechanism

Bashtrykov

Jankevicius

Jurkowska

et al. 2014

Journal of Biological Chemistry

117

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Background: UHRF1-mediated targeting of DNMT1 to replicated DNA is essential for DNA methylation. Results: We show here that UHRF1 stimulates the activity and specificity of DNMT1 by an allosteric mechanism. Conclusion: UHRF1 has multiple roles that support DNA methylation including targeting and regulation of the activity and specificity of DNMT1. Significance: Regulation of DNMT1 is essential for the rapid and faithful remethylation of DNA after replication.

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Section: Acknowledgment-the Dnmt1(731-1602) Construct and The Correspsupporting

confidence: 82%

The UHRF1 Protein Stimulates the Activity and Specificity of the Maintenance DNA Methyltransferase DNMT1 by an Allosteric Mechanism

Bashtrykov

Jankevicius

Jurkowska

et al. 2014

Journal of Biological Chemistry

117

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“…Further biochemical and structural experiments support RFTS as a DNA-competitive endogenous inhibitor of DNMT1 that must be removed from the DNA active site for DNMT1 activity. [32][33][34][35][36] In contrast to our biochemical insights into negative regulation by RFTS, CXXC was proposed as a nonmethylated DNA-binding inhibitor of DNMT1 activity. 37 Human genetics has the potential to help resolve DNMT1 domain function because an autosomal dominant hereditary sensory and autonomic neuropathy (HSAN1E) maps to the RFTS domain.…”

Section: Introductionmentioning

confidence: 99%

RFTS-deleted DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation

Mei

Brenner

2014

Cell Cycle

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Site-specific hypermethylation of tumor suppressor genes accompanied by genome-wide hypomethylation are epigenetic hallmarks of malignancy. However, the molecular mechanisms that drive these linked changes in DNA methylation remain obscure. DNA methyltransferase 1 (DNMT1), the principle enzyme responsible for maintaining methylation patterns is commonly dysregulated in tumors. Replication foci targeting sequence (RFTS) is an N-terminal domain of DNMT1 that inhibits DNA-binding and catalytic activity, suggesting that RFTS deletion would result in a gain of DNMT1 function. However, a substantial body of data suggested that RFTS is required for DNMT1 activity. Here, we demonstrate that deletion of RFTS alters DNMT1-dependent DNA methylation during malignant transformation. Compared to full-length DNMT1, ectopic expression of hyperactive DNMT1-DRFTS caused greater malignant transformation and enhanced promoter methylation with condensed chromatin structure that silenced DAPK and DUOX1 expression. Simultaneously, deletion of RFTS impaired DNMT1 chromatin association with pericentromeric Satellite 2 (SAT2) repeat sequences and produced DNA demethylation at SAT2 repeats and globally. To our knowledge, RFTS-deleted DNMT1 is the first single factor that can reprogram focal hypermethylation and global hypomethylation in parallel during malignant transformation. Our evidence suggests that the RFTS domain of DNMT1 is a target responsible for epigenetic changes in cancer.

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“…UHRF1 has a conserved function across vertebrates as an essential component of the DNA methylation machinery; it binds hemimethylated DNA generated during DNA replication and recruits DNA methyltransferase 1 (DNMT1) to methylate cytosines on newly synthesized DNA (Arita et al, 2008;Avvakumov et al, 2008;Bostick et al, 2007;Hashimoto et al, 2008;Qian et al, 2008;Sharif et al, 2007). UHRF1 also promotes the activity, specificity and degradation of DNMT1 (Bashtrykov et al, 2014;Berkyurek et al, 2014;Qin et al, 2011). Thus, UHRF1 serves to both promote and restrict DNA methylation and, consequently, both loss (Bostick et al, 2007;Feng et al, 2010;Sharif et al, 2007) and overexpression (Mudbhary et al, 2014) of UHRF1 restructures the methylome.…”

Section: Introductionmentioning

confidence: 99%

DNA hypomethylation induces a DNA replication-associated cell cycle arrest to block hepatic outgrowth in uhrf1 mutant zebrafish embryos

et al. 2015

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UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 to hemimethylated DNA during replication and is essential for maintaining DNA methylation. uhrf1 mutant zebrafish have global DNA hypomethylation and display embryonic defects, including a small liver, and they die as larvae. We make the surprising finding that, despite their reduced organ size, uhrf1 mutants express high levels of genes controlling S-phase and have many more cells undergoing DNA replication, as measured by BrdU incorporation. In contrast to wild-type hepatocytes, which are continually dividing during hepatic outgrowth and thus dilute the BrdU label, uhrf1 mutant hepatocytes retain BrdU throughout outgrowth, reflecting cell cycle arrest. Pulse-chase-pulse experiments with BrdU and EdU, and DNA content analysis indicate that uhrf1 mutant cells undergo DNA re-replication and that apoptosis is the fate of many of the rereplicating and arrested hepatocytes. Importantly, the DNA rereplication phenotype and hepatic outgrowth failure are preceded by global loss of DNA methylation. Moreover, uhrf1 mutants are phenocopied by mutation of dnmt1, and Dnmt1 knockdown in uhrf1 mutants enhances their small liver phenotype. Together, these data indicate that unscheduled DNA replication and failed cell cycle progression leading to apoptosis are the mechanisms by which DNA hypomethylation prevents organ expansion in uhrf1 mutants. We propose that cell cycle arrest leading to apoptosis is a strategy that restricts propagation of epigenetically damaged cells during embryogenesis.

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The DNA Methyltransferase Dnmt1 Directly Interacts with the SET and RING Finger-associated (SRA) Domain of the Multifunctional Protein Uhrf1 to Facilitate Accession of the Catalytic Center to Hemi-methylated DNA

Cited by 110 publications

References 23 publications

The UHRF1 Protein Stimulates the Activity and Specificity of the Maintenance DNA Methyltransferase DNMT1 by an Allosteric Mechanism

The UHRF1 Protein Stimulates the Activity and Specificity of the Maintenance DNA Methyltransferase DNMT1 by an Allosteric Mechanism

RFTS-deleted DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation

DNA hypomethylation induces a DNA replication-associated cell cycle arrest to block hepatic outgrowth in uhrf1 mutant zebrafish embryos

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