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

Bashtrykov, Pavel; Jankevicius, Gytis; Jurkowska, Renata Z.; Ragozin, Sergey; Jeltsch, Albert

doi:10.1074/jbc.m113.528893

Cited by 119 publications

(117 citation statements)

References 55 publications

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“…To our knowledge, there are at least 3 known RAPs including ubiquitin-like containing PHD and RING finger domain protein 1 (UHRF1), 29,30,35 ubiquitinspecific-processing protease 7 (USP7) 53 and N-a-acetyltransferase 10 NatA catalytic subunit (NAA10). 54 These proteins have been shown to recruit DNMT1 to specific loci and stimulate its methylation activity, causing site-specific hypermethylation.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Mei

Brenner

2014

Cell Cycle

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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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“…From these observations, we speculate that the SRA domain of UHRF2 uses two pockets to bind 5hmC and ZNF618 at the same time. In fact, studies have shown that the SRA domain of UHRF1 could bind 5mC and DNMT1 using two different pockets (22,23). In this scenario, dual binding of 5hmC and ZNF618 will not only strengthen the chromatin binding of UHRF2, but might also provide additional regulation where UHRF2 is localized through the ZNF618 N-terminal two zinc figures recognizing specific genomic sequences.…”

Section: Discussionmentioning

confidence: 99%

“…UHRF1 loads DNMT1 to hemi-methylated DNA regions after DNA replication (22,23) to methylate the nascent strand. In addition, UHRF1 interacts with Topoisomerase II, which resolves the catenated DNA after DNA replication to allow efficient DNA methylation (24).…”

mentioning

confidence: 99%

Zinc Finger Protein 618 Regulates the Function of UHRF2 (Ubiquitin-like with PHD and Ring Finger Domains 2) as a Specific 5-Hydroxymethylcytosine Reader

Liu

Zhang

Kuang

et al. 2016

Journal of Biological Chemistry

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5-Hydroxymethylcytosine (5hmC) is an epigenetic modification that is generated by ten-eleven translocation (TET) protein-mediated oxidation of 5-methylcytosine (5mC). 5hmC is associated with transcription regulation and is decreased in many cancers including melanoma. Accumulating evidence has suggested that 5hmC is functionally distinct from 5mC. Ubiquitin-like with PHD and ring finger domains 2 (UHRF2) is the first known specific 5hmC reader that has higher affinity to 5hmC than 5mC, suggesting that UHRF2 might mediate 5hmC's function. Structural analysis has revealed the molecular mechanism of UHRF2-5hmC binding in vitro, but it is not clear how UHRF2 recognizes 5hmC in vivo. In this study, we have identified zinc figure protein 618 (ZNF618) as a novel binding partner of UHRF2. ZNF618 specifically interacts with UHRF2 but not its paralog UHRF1. Importantly, ZNF618 co-localizes with UHRF2 at genomic loci that are enriched for 5hmC. The ZNF618 chromatin localization is independent of its interaction with UHRF2 and is through its first two zinc fingers. Instead, ZNF618 regulates UHRF2 chromatin localization. Collectively, our study suggests that ZNF618 is a key protein that regulates UHRF2 function as a specific 5hmC reader in vivo.DNA methylation is an epigenetic modification that regulates multiple cellular processes including gene transcription, genomic imprinting, and X chromosome inactivation. DNA methylation mainly exists as 5-methylcytosine (5mC) 3 in CpG context, which is established and maintained by three major DNA methyltransferases in cells (1). 5mC can be oxidized by ten-eleven translocation (TET) proteins to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) (2-4). These 5mC derivatives are believed to be intermediates of DNA demethylation (5).5hmC is much more abundant than others among three 5mC derivatives (6). It is not a favorable substrate for further oxidation and is therefore most stable (7,8). It is widely present in many cell types and tissues and is particularly enriched in neurons and stem cells (9, 10). 5hmC and 5mC have different genome-wide distributions and are associated with different transcriptional outcome (11-16). Loss of 5hmC, but not 5mC, is a hallmark of many cancers including melanoma (17). These studies suggest that 5hmC is more than just an intermediate of DNA demethylation, but is an important epigenetic modification that is distinct from 5mC.The function of 5hmC is still not clear, largely due to the lack of knowledge about 5hmC readers. Previous studies have shown that some 5mC readers, such as UHRF1 and MeCP2, can also bind 5hmC (18,19). These proteins use the same 5mC-binding domain to interact with 5hmC, but the 5hmC binding affinity was similar to or weaker than their 5mC binding affinities (18,19). Recent proteomic approaches have revealed several 5hmC-specific binding proteins that have higher affinity to 5hmC than 5mC (20). UHRF2 is the best characterized one and its SRA domain has 3-fold higher binding affinity to 5hmC than 5m...

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

Cited by 119 publications

References 55 publications

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

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

Zinc Finger Protein 618 Regulates the Function of UHRF2 (Ubiquitin-like with PHD and Ring Finger Domains 2) as a Specific 5-Hydroxymethylcytosine Reader

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