A fluorescent bimolecular complementation screen reveals MAF1, RNF7 and SETD3 as PCNA-associated proteins in human cells

Cooper, Simon; Hodimont, E.; Green, Catherine

doi:10.1080/15384101.2015.1053667

Cited by 25 publications

(27 citation statements)

References 79 publications

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“…SETD3 accumulates after the peak of cyclin E1, a critical regulator controlling G 1 /S transition, but before the induction of cyclin B1, a critical regulator of G 2 /M transition, implying that SETD3 functions from the S phase to G 2 phase. Consistently, a recent study showed that SETD3 interacted with proliferating cell nuclear antigen, a key component of the DNA replication machinery, indicating its potential roles in DNA replication and DNA repair (36). It has been reported that both zebrafish and mouse homologs of SETD3 may catalyze H3K4 or H3K36 mono-and dimethylation in vitro (31,32), and H3K4 and H3K36 methylations are associated with DNA replication and DNA repair (37-39).…”

Section: Discussionmentioning

confidence: 68%

Cell cycle-dependent degradation of the methyltransferase SETD3 attenuates cell proliferation and liver tumorigenesis

Cheng

Hao

Shu

et al. 2017

Journal of Biological Chemistry

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Histone modifications, including lysine methylation, are epigenetic marks that influence many biological pathways. Accordingly, many methyltransferases have critical roles in various biological processes, and their dysregulation is often associated with cancer. However, the biological functions and regulation of many methyltransferases are unclear. Here, we report that a human homolog of the methyltransferase SET (U(var), nhancer of zeste, andrithorax) domain containing 3 (SETD3) is cell cycle-regulated; SETD3 protein levels peaked in S phase and were lowest in M phase. We found that the β-isoform of the tumor suppressor F-box and WD repeat domain containing 7 (FBXW7β) specifically mediates SETD3 degradation. Aligning the SETD3 sequence with those of well known FBXW7 substrates, we identified six potential non-canonical Cdc4 phosphodegrons (CPDs), and one of them, CPD1, is primarily phosphorylated by the kinase glycogen synthase kinase 3 (GSK3β), which is required for FBXW7β-mediated recognition and degradation. Moreover, depletion or inhibition of GSK3β or FBXW7β resulted in elevated SETD3 levels. Mutations of the phosphorylated residues in CPD1 of SETD3 abolished the interaction between FBXW7β and SETD3 and prevented SETD3 degradation. Our data further indicated that SETD3 levels positively correlated with cell proliferation of liver cancer cells and liver tumorigenesis in a xenograft mouse model, and that overexpression of FBXW7β counteracts the SETD3's tumorigenic role. We also show that SETD3 levels correlate with cancer malignancy, indicated by SETD3 levels that the 54 liver tumors are 2-fold higher than those in the relevant adjacent tissues. Collectively, these data elucidated that a GSK3β-FBXW7β-dependent mechanism controls SETD3 protein levels during the cell cycle and attenuates its oncogenic role in liver tumorigenesis.

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Section: Discussionmentioning

confidence: 68%

Cell cycle-dependent degradation of the methyltransferase SETD3 attenuates cell proliferation and liver tumorigenesis

Cheng

Hao

Shu

et al. 2017

Journal of Biological Chemistry

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“…Additionally, Pol III activity may be affected by other players modulating the MAF1 effect, such as the previously proposed casein kinase 2 (Boguta and Graczyk 2011), or by putative MAF1 binding partners brought in close proximity of Pol III genes. For example, MAF1 has recently been shown to interact with PCNA (Cooper et al 2015), a member of the DNA sliding clamp family with the ability to inhibit EP300 acetyltransferase activity (Hong and Chakravarti 2003). It is conceivable that MAF1-delivered PCNA could repress transcription of Pol III, which contains a PCNA binding site in the POLR3E (Rpc5) subunit (Gilljam et al 2009), by preventing histone acetylation in the vicinity of Pol III genes.…”

Section: A Model For Maf1 Repression Of Transcribing Pol IIImentioning

confidence: 99%

Human MAF1 targets and represses active RNA polymerase III genes by preventing recruitment rather than inducing long-term transcriptional arrest

et al. 2016

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RNA polymerase III (Pol III) is tightly controlled in response to environmental cues, yet a genomic-scale picture of Pol III regulation and the role played by its repressor MAF1 is lacking. Here, we describe genome-wide studies in human fibroblasts that reveal a dynamic and gene-specific adaptation of Pol III recruitment to extracellular signals in an mTORC1-dependent manner. Repression of Pol III recruitment and transcription are tightly linked to MAF1, which selectively localizes at Pol III loci, even under serum-replete conditions, and increasingly targets transcribing Pol III in response to serum starvation. Combining Pol III binding profiles with EU-labeling and high-throughput sequencing of newly synthesized small RNAs, we show that Pol III occupancy closely reflects ongoing transcription. Our results exclude the long-term, unproductive arrest of Pol III on the DNA as a major regulatory mechanism and identify previously uncharacterized, differential coordination in Pol III binding and transcription under different growth conditions.

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Section: Ash1l: Hox Gene Activator With Emerging Role In Cancermentioning

confidence: 99%

“…SETD3 expression is lower in renal cell tumors than normal renal tissues, and low expression of SETD3 is associated with shorter survival in renal cell carcinoma patients [118]. SETD3 has been implicated in DNA replication and repair due to its interaction with proliferating cell nuclear antigen, a conserved factor involved in DNA synthesis [119].H3K36-specific SET domains: structural considerations for inhibitor development Structural details of target proteins are extremely valuable in the development of potent and specific inhibitors. For the H3K36-specific KMTases, structural studies of the catalytic SET domain have revealed valuable information to jumpstart inhibitor development.…”

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confidence: 99%

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors. Nevertheless, potent inhibitors for most H3K36 KMTases have not yet been developed, underlining the challenges associated with this target class. As we now have strong evidence linking H3K36 KMTases to cancer, drug development efforts are predicted to yield novel compounds in the near future. Cellular development and differentiation are controlled by post-translational modifications on DNA and histone proteins, forming an epigenetic (above the genes) regulatory network. Disruption of epigenetic pathways is a nearly universal feature of cancer, causing aberrations in gene expression and genome integrity (reviewed in [1]). A key group of epigenetic enzymes disrupted in cancer is the lysine methyltransferases (KMTases), which install methyl groups on histone proteins. In cancer cells, methylation performed by KMTases drives proliferation and halts differentiation by modifying gene transcription and other DNA-templated processes [2][3][4]. Over the past decade, KMTases have emerged as important drug targets for both industrial and academic research groups. Some progress has been made, most notably by selective inhibitors for the EZH2 and DOT1L KMTases that have reached clinical trials for the treatment of nonHodgkin lymphoma and acute leukemia, respectively [5,6]. Nevertheless, selective and cell permeable inhibitors for many KMTases remain unavailable.Methylation at H3K36 represents a particularly important chromatin mark implicated in diverse forms of cancer. KMTases with specificity toward H3K36 are overexpressed in cancer cells and have been characterized as regulators of cell growth, differentiation, stemness and DNA repair pathways [7][8][9]. However, very few selective and cell-active small molecule inhibitors of H3K36-specfic KMTases have been reported to date. In this article, we provide an overview of cellular pathways involving H3K36 methylation and discuss the diverse functions carried out by the eight different human H3K36-specific KMTases. Then we analyze structural characteristics of the catalytic SET domain of H3K36 KMTases and evaluate prospects for their inhibition by small molecules. Review Rogawski, Grembecka & Cierpicki We conclude with a discussion of the challenges and o pportunities for targeting these proteins. SPECIAL FOCUS y Epigenetic drug discovery H3K36 methylation regulates diverse processes implicated in cancerH3K36 methylation participates in a wide variety of nuclear pathways. Many of these processes, including transcriptional regulation, alternative spli...

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A fluorescent bimolecular complementation screen reveals MAF1, RNF7 and SETD3 as PCNA-associated proteins in human cells

Cited by 25 publications

References 79 publications

Cell cycle-dependent degradation of the methyltransferase SETD3 attenuates cell proliferation and liver tumorigenesis

Cell cycle-dependent degradation of the methyltransferase SETD3 attenuates cell proliferation and liver tumorigenesis

Human MAF1 targets and represses active RNA polymerase III genes by preventing recruitment rather than inducing long-term transcriptional arrest

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

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