DNMT1 Stability Is Regulated by Proteins Coordinating Deubiquitination and Acetylation-Driven Ubiquitination

Du, Zhanwen; Song, Jing; Wang, Yong; Zhao, Yiqing; Guda, Kishore; Yang, Shuming; Kao, Hung Ying; Xu, Yan; Willis, Joseph E.; Markowitz, Sanford D.; Sedwick, David; Ewing, Rob M.; Wang, Zhenghe

doi:10.1126/scisignal.2001462

Cited by 296 publications

(373 citation statements)

References 33 publications

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“…UHRF1 regulates transcription by regulating DNA methylation and histone modification. UHRF1 also possesses E3 ubiquitin ligase activity and ubiquitinates histones and DNA methyltransferase 1 (DNMT1), thereby regulating the chromatin structure and stability of DNMT1 (10,11). UHRF1 plays key roles in multiple biological processes, including proliferation and development.…”

mentioning

confidence: 99%

Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1

Taniue

Kurimoto

Sugimasa

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

127

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Many long noncoding RNAs (lncRNAs) are reported to be dysregulated in human cancers and play critical roles in tumor development and progression. Furthermore, it has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic loci or by controlling transcriptional or posttranscriptional processes. Here we show that an lncRNA termed UPAT [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domaincontaining protein 1 (UHRF1) Protein Associated Transcript] is required for the survival and tumorigenicity of colorectal cancer cells. UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its β-transducin repeat-containing protein (TrCP)-mediated ubiquitination. Furthermore, we demonstrate that UHRF1 up-regulates Stearoyl-CoA desaturase 1 and Sprouty 4, which are required for the survival of colon tumor cells. Our study provides evidence for an lncRNA that regulates protein ubiquitination and degradation and thereby plays a critical role in the survival and tumorigenicity of tumor cells. Our results suggest that UPAT and UHRF1 may be promising molecular targets for the therapy of colon cancer.A mong the RNA products transcribed from the mammalian genome are numerous long noncoding RNAs (lncRNAs)-that is, RNAs longer than 200 nucleotides with little or no protein-coding potential (1, 2). Many lncRNAs are expressed in a developmentally regulated and cell type-dependent manner (3, 4). Increasing evidence suggests that lncRNAs play critical roles in a diverse set of biological processes, including proliferation, differentiation, embryogenesis, neurogenesis, and stem cell pluripotency (5, 6).It has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic regions (2). It has also been shown that many lncRNAs regulate transcription by modulating the activity of transcriptional regulators (1, 6-8). lncRNAs also regulate various posttranscriptional processes, including splicing, transport, translation, and degradation of mRNA. Furthermore, recent studies have shown that a number of lncRNAs play critical roles in tumor development and progression.UHRF1 [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domain-containing protein 1] is an epigenetic factor that consists of multiple domains (9). UHRF1 regulates transcription by regulating DNA methylation and histone modification. UHRF1 also possesses E3 ubiquitin ligase activity and ubiquitinates histones and DNA methyltransferase 1 (DNMT1), thereby regulating the chromatin structure and stability of DNMT1 (10, 11). UHRF1 plays key roles in multiple biological processes, including proliferation and development. Furthermore, UHRF1 is overexpressed in various tumors, including colon, breast, bladder, prostate, and lung cancers, and plays a critical role in the proliferation and survival of tumor cells (9).In the present study, we attempted to identify lncRNAs criti...

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mentioning

confidence: 99%

Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1

Taniue

Kurimoto

Sugimasa

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

127

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“…38,39 DNMT1 is further stabilized by a UHRF1/HDAC1 complex containing USP7 deubiquitinase, also called "herpes virus-associated ubiquitin-specific protease," which prevents DNMT1 proteosomal degradation. 39 In addition, UHRF1 both reinforces silencing at methylated CpG sites and ensures transcription at unmethylated CpG islands. CpG islands are open regions of DNA that are highly accessible to transcription initiation complexes.…”

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confidence: 99%

Basic concepts of epigenetics

Mazzio

Soliman²

2012

Epigenetics

204

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“…Whereas USP7 stabilizes DNMT1 and facilitates cell cycle progression, Tip60 acetylates DNMT1 and promotes the degradation of DNMT1 by its E3 ligase UHRF1 (ref. 44). Besides having critical roles in proliferation and apoptosis, both Tip60 and USP7 have recently been implicated in cellular differentiation.…”

Section: Discussionmentioning

confidence: 99%

Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60

et al. 2013

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Transcriptional coregulators, including the acetyltransferase Tip60, have a key role in complex cellular processes such as differentiation. Whereas post-translational modifications have emerged as an important mechanism to regulate transcriptional coregulator activity, the identification of the corresponding demodifying enzymes has remained elusive. Here we show that the expression of the Tip60 protein, which is essential for adipocyte differentiation, is regulated through polyubiquitination on multiple residues. USP7, a dominant deubiquitinating enzyme in 3T3-L1 adipocytes and mouse adipose tissue, deubiquitinates Tip60 both in intact cells and in vitro and increases Tip60 protein levels. Furthermore, inhibition of USP7 expression and activity decreases adipogenesis. Transcriptome analysis reveals several cell cycle genes to be co-regulated by both Tip60 and USP7. Knockdown of either factor results in impaired mitotic clonal expansion, an early step in adipogenesis. These results reveal deubiquitination of a transcriptional coregulator to be a key mechanism in the regulation of early adipogenesis.

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DNMT1 Stability Is Regulated by Proteins Coordinating Deubiquitination and Acetylation-Driven Ubiquitination

Cited by 296 publications

References 33 publications

Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1

Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1

Basic concepts of epigenetics

Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60

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