The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1

Felle, Max; Joppien, Saskia; Németh, Attila; Diermeier, Sarah D.; Thalhammer, Verena; Dobner, Thomas; Kremmer, Elisabeth; Kappler, Roland; Längst, Gernot

doi:10.1093/nar/gkr528

Cited by 167 publications

(190 citation statements)

References 54 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%

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%

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

Mei

Brenner

2014

Cell Cycle

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“…Changes in methylation are also associated with aging, cellular senescence, and tumorigenesis (9,(60)(61)(62)(63). Therefore, proper regulation of DNMT1 levels and activity is critical for maintaining cells in a differentiated state and preventing tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

HBP1-Mediated Transcriptional Regulation of DNA Methyltransferase 1 and Its Impact on Cell Senescence

Pan

Chen

Roth

et al. 2013

Molecular and Cellular Biology

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bThe activity of DNA methyltransferase 1 (DNMT1) is associated with diverse biological activities, including cell proliferation, senescence, and cancer development. In this study, we demonstrated that the HMG box-containing protein 1 (HBP1) transcription factor is a new repressor of DNMT1 in a complex mechanism during senescence. The DNMT1 gene contains an HBP1-binding site at bp ؊115 to ؊134 from the transcriptional start site. HBP1 repressed the endogenous DNMT1 gene through sequencespecific binding, resulting in both gene-specific (e.g., p16INK4 ) and global DNA hypomethylation changes. The HBP1-mediated repression by DNMT1 contributed to replicative and premature senescence, the latter of which could be induced by Ras and HBP1 itself. A detailed investigation unexpectedly revealed that HBP1 has dual and complex transcriptional functions, both of which contribute to premature senescence. HBP1 both repressed the DNMT1 gene and activated the p16 gene in premature senescence. The opposite transcriptional functions proceeded through different DNA sequences and differential protein acetylation. While intricate, the reciprocal partnership between HBP1 and DNMT1 has exceptional importance, since its abrogation compromises senescence and promotes tumorigenesis. Together, our results suggest that the HBP1 transcription factor orchestrates a complex regulation of key genes during cellular senescence, with an impact on overall DNA methylation state. Epigenetic alterations have essential roles in determining gene expression patterns and in setting the environment for activators or repressors to function appropriately. DNA methylation has been associated with cancer and senescence (1-4). Cellular senescence is characterized by a permanent cell cycle arrest and the acquisition of distinct morphological, physiological, and epigenetic changes in response to events such as telomere attrition, aberrant oncogene activation, or abrogation of tumor suppressor gene functions. Senescence is a tumor-suppressive process the abrogation of which enables the path to tumorigenesis (5-8). Although seemingly two distinct phenomena, cellular senescence and cancer share similarly altered global epigenetic profiles comprising complex changes in DNA methylation, involving both hypomethylation and hypermethylation of certain genes and sequences. The establishment of DNA methylation during DNA replication and DNA repair is catalyzed by a family of DNA methyltransferases (e.g., DNMT1, DNMT3A, and DNMT3B). In particular, DNMT1 mRNA expression is significantly elevated in different cancers and is regarded as a maintenance methylase (9-11). In senescence, the levels of DNA methylation and DNMT1 protein decline in concert with aging (12-15). Yet, the mechanism of age-dependent DNA methylation changes remains unknown. In this study, we found an unexpected connection to the HBP1 transcription factor, which our previous studies had linked to premature senescence (16).HBP1 is a member of the sequence-specific high-mobilitygroup (HMG) family of transcript...

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“…3,4 The targeting of Dnmt1 to hemimethylated DNA is promoted by PCNA, UHRF1, and USP7. [5][6][7] Dnmt1 also interacts with Dnmt3a and Dnmt3b and multiple additional silencing proteins, including the HDAC1 and HDAC2, heterochromatin protein-1, and histone lysine methyltransferases and methyl-binding domain proteins. [5][6][7] Dnmt1 stability and function are regulated by several posttranslational modifications, including phosphorylation, acetylation, ubiquitylation, methylation, and sumoylation.…”

Section: Introductionmentioning

confidence: 99%

Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity

Wang

Liu²,

Beier

et al. 2013

Blood

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The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1

Cited by 167 publications

References 54 publications

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

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

HBP1-Mediated Transcriptional Regulation of DNA Methyltransferase 1 and Its Impact on Cell Senescence

Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity

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