Regulation of DNA methyltransferase 1 by interactions and modifications

Qin, Weihua; Leonhardt, Heinrich; Pichler, Garwin

doi:10.4161/nucl.2.5.17928

Cited by 88 publications

(101 citation statements)

References 108 publications

(145 reference statements)

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“…29 The maintenance methyltransferase can also be modified by covalent attachment of small ubiquitinlike modifier (SUMO) proteins, a process referred to as SUMOylation. 30 The effects of these modifications are site specific and dependent on the enzymatic players involved.…”

Section: Regulation Of Dnmtsmentioning

confidence: 99%

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

Johnson

Akman²,

Calimport³

et al. 2012

Rejuvenation Research

307

218

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DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-l-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.

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Section: Regulation Of Dnmtsmentioning

confidence: 99%

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

Johnson

Akman²,

Calimport³

et al. 2012

Rejuvenation Research

307

218

View full text Add to dashboard Cite

show abstract

“…DNMT1 is regulated by ubiquitination-dependent degradation at the proteasome (33,34). Treatment of the ATM-reconstituted Rb Ϫ/Ϫ ; ATM Ϫ/Ϫ MEFs with a proteasome inhibitor, MG132, increased the DNMT1 level in the nucleus and enhanced its colocalization with ATM pS1891 in a time-dependent manner (Fig.…”

Section: Atm Status Affects P16mentioning

confidence: 99%

ATM Mediates pRB Function To Control DNMT1 Protein Stability and DNA Methylation

Shamma

Suzuki

Hayashi

et al. 2013

Molecular and Cellular Biology

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eThe retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many chromatin modifiers. However, the biological and clinical significance of this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in an Rb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction of Rb and ATM regulates DNMT1 protein stability and hence controls the DNA methylation status in the promoters of at least the Ink4a, Shc2, FoxO6, and Noggin genes. Furthermore, we demonstrate that inactivation of pRB promotes Tip60 (acetyltransferase)-dependent ATM activation; allows activated ATM to physically bind to DNMT1, forming a complex with Tip60 and UHRF1 (E3 ligase); and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of the pRB pathway in coordination with aberration in the DNA damage response deregulates DNMT1 stability, leading to an abnormal DNA methylation pattern and malignant progression.T he retinoblastoma tumor suppressor gene (RB) is prevalently mutated at the initiation of retinoblastoma, osteosarcoma, and small-cell lung cancer. However, in the majority of human cancers, retinoblastoma protein (pRB) inactivation is frequently detected during tumor progression and is implicated in various facets of malignant behaviors (1). This suggests that pRB may possess more functions beyond its well-known roles in the control of the cell cycle and differentiation (2, 3). Previous studies demonstrated the direct interaction of pRB with a number of epigenetic modifiers carrying the LXCXE motif, including DNA methyltransferase 1 (DNMT1) (4, 5). pRB has been suggested to play a certain role in nuclear reprogramming in embryonic stem (ES) cells, induced pluripotent stem (iPS) cells, mouse embryonic fibroblasts (MEFs), as well as tumor cells (6-10). Furthermore, RB loss was recently shown to contribute to the progression of human retinoblastoma via epigenetic modifications (11). However, the precise mechanism and target genes of the pRB epigenetic function are still largely unknown.pRB inactivation induces DNA double-strand breaks (DSBs) via multiple pathways (12-17). The MRN (Mre11, Rad50, and NBS1) sensor complex detects DSBs, rapidly activates ataxia telangiectasia mutated (ATM), and recruits ATM to the site of DSBs. ATM then activates a number of transducers, such as MDC1, 53BP1, and BRCA1, and effector kinases, such as Chk2. These proteins subsequently activate molecules required for DSB repair, including the histone variant H2AX (18)(19)(20). Our previous study demonstrated that some components of the DNA damage response (DDR) are activated upon Rb loss in vivo and in vitro (15). We therefore speculated that ATM might mediate pRB functions to regulate the DDR pathway.C cell (calcitonin-producing cell) tumors developed in Rb ϩ/Ϫ mice are precancerous and display many features of the DDR and cellular s...

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“…Expression levels of these proteins are directly related to the DNMT1 stability and activity. 3 Song et al 4 found that HAUSP is overexpressed in prostate cancer and more importantly that high levels of HAUSP are directly correlated with tumor aggressiveness.…”

mentioning

confidence: 99%

Does Wnt/β-catenin pathway contribute to the stability of DNMT1 expression in urological cancer cell lines?

Varol

Konac

Bilen

2014

Exp Biol Med (Maywood)

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DNA methylation is considered as one of the most important epigenetic mechanisms and it is catalyzed by DNA methyltransferases (DNMTs). DNMT1 abundance has been frequently seen in urogenital system tumors but the reasons for this abundance are not well understood. We aimed to look into the effects of Wnt/b-catenin signaling pathway on overexpression of DNMT1 and aberrant expression of UHRF1 and HAUSP which are responsible for stability of DNMT1 at transcriptional and protein levels in urogenital cancers. In this context, firstly, Wnt/b-catenin signaling pathway was activated by using SB216763 which is a glycogen synthase kinase-3 (GSK3) b inhibitor. Cell proliferation levels in bladder cancer cells, renal cell carcinoma, and prostate cancer cells treated with GSK3b inhibitor (SB216763) were detected by WST-1 reagent. WIF-1 gene methylation profile was determined by methylation-specific PCR (MSP); expression levels of target genes -catenin and WIF-1 by real-time PCR; and protein levels of -catenin, DNMT1, pGSK3(Ser9), HAUSP, and UHRF1 by Western Blot. Our results indicated that treatment with SB216763 caused an increased cell proliferation at low dose. mRNA levels of -catenin increased after treatment with SB216273 and protein levels of pGSK3b(Ser9), b-catenin, and DNMT1 increased in comparison to control. HAUSP and UHRF1 were either up-regulated or down-regulated at the same doses depending on the type of cancer. Also, we showed that protein levels of DNMT1, b-catenin, HAUSP, and UHRF1 decreased after re-expression of WIF-1 following treatment with DAC. In Caki-2 cells, -catenin pathway might have accounted for the stability of DNMT1 expression, whereas such relation is not valid for T24 and PC3 cells. Our findings may offer a new approach for determination of molecular effects of Wnt/b-catenin signal pathway on DNMT1. This may allow us to identify new molecular targets for the treatment of urogenital cancers.

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Regulation of DNA methyltransferase 1 by interactions and modifications

Cited by 88 publications

References 108 publications

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

ATM Mediates pRB Function To Control DNMT1 Protein Stability and DNA Methylation

Does Wnt/β-catenin pathway contribute to the stability of DNMT1 expression in urological cancer cell lines?

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