A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20

Blank, Michael; Tang, Yi; Yamashita, Masaru; Burkett, Sandra; Cheng, Steven Y.; Zhang, Ying E.

doi:10.1038/nm.2596

Cited by 142 publications

(174 citation statements)

References 45 publications

(57 reference statements)

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“…In so much as the defect in HRR is able to trigger sufficient genomic instability to accelerate cancer-promoting mutations (Cousineau and Belmaaza, 2007), the dysfunctional SUPT16H pathway could conceivably increase cancer susceptibility. Consistent with this prediction, recent studies have shown that tumorigenesis is promoted by dysfunction of Smurf2, a HECT-domain E3 ubiquitin ligase, which induces RNF20 degradation by proteasomal machinery (Blank et al, 2012). Similarly, CDC73, which regulates H2B ubiquitylation through its interaction with RNF20, is mutated and/or downregulated in various types of tumors (Hahn et al, 2012).…”

Section: C922smentioning

confidence: 73%

Histone chaperone FACT regulates homologous recombination by chromatin remodeling through interaction with RNF20

Oliveira

Nakamura

Ikura

et al. 2013

Journal of Cell Science

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The E3 ubiquitin ligase RNF20 regulates chromatin structure through ubiquitylation of histone H2B, so that early homologous recombination repair (HRR) proteins can access the DNA in eukaryotes during repair. However, it remains unresolved how RNF20 itself approaches the DNA in the presence of chromatin structure. Here, we identified the histone chaperone FACT as a key protein in the early steps of HRR. Depletion of SUPT16H, a component of FACT, caused pronounced defects in accumulations of repair proteins and, consequently, decreased HRR activity. This led to enhanced sensitivity to ionizing radiation (IR) and mitomycin-C in a fashion similar to RNF20-deficient cells, indicating that SUPT16H is essential for RNF20-mediated pathway. Indeed, SUPT16H directly bound to RNF20 in vivo, and mutation at the RING-finger domain in RNF20 abolished its interaction and accumulation, as well as that of RAD51 and BRCA1, at sites of DNA double-strand breaks (DSBs), whereas the localization of SUPT16H remained intact. Interestingly, PAF1, which has been implicated in transcription as a mediator of FACT and RNF20 association, was dispensable for DNA-damage-induced interaction of RNF20 with SUPT16H. Furthermore, depletion of SUPT16H caused pronounced defects in RNF20-mediated H2B ubiquitylation and thereby, impaired accumulation of the chromatin remodeling factor SNF2h. Consistent with this observation, the defective phenotypes of SUPT16H were effectively counteracted by enforced nucleosome relaxation. Taken together, our results indicate a primary role of FACT in RNF20 recruitment and the resulting chromatin remodeling for initiation of HRR.

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Section: C922smentioning

confidence: 73%

Histone chaperone FACT regulates homologous recombination by chromatin remodeling through interaction with RNF20

Oliveira

Nakamura

Ikura

et al. 2013

Journal of Cell Science

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“…Further studies in HCT116 cells and nude mice suggested that the autoneddylation of Smurf1 and the ubiquitin ligase activity of Smurf1 were critical for its tumour-promoting function. In contrast to the tumourpromoting role of Smurf1, Smurf2 has been suggested to function as a tumour suppressor gene since ablation of Smurf2 in mice resulted in increased susceptibility to various types of cancers in aged mice 61 . We noted that the NAE inhibitor MLN4924 has been recently identified as a novel approach to the treatment of acute myeloid leukaemia, head and neck cancer and liver cancer [62][63][64] .…”

Section: Discussionmentioning

confidence: 99%

The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis

et al. 2014

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Neddylation, the covalent attachment of ubiquitin-like protein Nedd8, of the Cullin-RING E3 ligase family regulates their ubiquitylation activity. However, regulation of HECT ligases by neddylation has not been reported to date. Here we show that the C2-WW-HECT ligase Smurf1 is activated by neddylation. Smurf1 physically interacts with Nedd8 and Ubc12, forms a Nedd8-thioester intermediate, and then catalyses its own neddylation on multiple lysine residues. Intriguingly, this autoneddylation needs an active site at C426 in the HECT N-lobe. Neddylation of Smurf1 potently enhances ubiquitin E2 recruitment and augments the ubiquitin ligase activity of Smurf1. The regulatory role of neddylation is conserved in human Smurf1 and yeast Rsp5. Furthermore, in human colorectal cancers, the elevated expression of Smurf1, Nedd8, NAE1 and Ubc12 correlates with cancer progression and poor prognosis. These findings provide evidence that neddylation is important in HECT ubiquitin ligase activation and shed new light on the tumour-promoting role of Smurf1.

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“…Aberrant H2Bub1 levels can affect development (Wright et al 2011), apoptosis (Walter et al 2010), stem cell differentiation (Buszczak et al 2009;Fuchs et al 2012;Karpiuk et al 2012), viral infection outcome (Sarkari et al 2009;Fonseca et al 2012), and cell cycle progression (Hwang and Madhani 2009) and can promote cancer Blank et al 2012;Johnsen 2012;. Several mechanisms have been proposed to underlie the ability of H2Bub1 to exert those diverse effects, including impact on higher-order chromatin organization (Fierz et al 2011), altered nucleosome stability (Chandrasekharan et al 2009), regulation of H2A-H2B dimer displacement (Pavri et al 2006), and modulation of the recruitment of specific factors to chromatin (Shema-Yaacoby et al 2013).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate

et al. 2014

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Various histone modifications decorate nucleosomes within transcribed genes. Among these, monoubiquitylation of histone H2B (H2Bub1) and methylation of histone H3 on lysines 36 (H3K36me2/3) and 79 (H3K79me2/3) correlate positively with gene expression. By measuring the progression of the transcriptional machinery along genes within live cells, we now report that H2B monoubiquitylation occurs cotranscriptionally and accurately reflects the advance of RNA polymerase II (Pol II). In contrast, H3K36me3 and H3K79me2 are less dynamic and represent Pol II movement less faithfully. High-resolution ChIP-seq reveals that H2Bub1 levels are selectively reduced at exons and decrease in an exon-dependent stepwise manner toward the 39 end of genes. Exonic depletion of H2Bub1 in gene bodies is highly correlated with Pol II pausing at exons, suggesting elongation rate changes associated with intron-exon structure. In support of this notion, H2Bub1 levels were found to be significantly correlated with transcription elongation rates measured in various cell lines. Overall, our data shed light on the organization of H2Bub1 within transcribed genes and single out H2Bub1 as a reliable marker for ongoing transcription elongation.

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A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20

Cited by 142 publications

References 45 publications

Histone chaperone FACT regulates homologous recombination by chromatin remodeling through interaction with RNF20

Histone chaperone FACT regulates homologous recombination by chromatin remodeling through interaction with RNF20

The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis

Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate

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