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

In addition to allelic mutations, cancers are known to harbor alterations in their chromatin landscape. Here we show that genomic ablation of Smad ubiquitin regulatory factor 2 (Smurf2), a HECT-domain E3 ubiquitin ligase, results in dysregulation of both the DNA damage response and genomic stability, culminating in increased susceptibility to various types of cancers in aged mice. We show that Smurf2 regulates the monoubiquitination of histone H2B as well as the trimethylation of histone H3 at Lys4 and Lys79 by targeting ring finger protein 20 (RNF20) for proteasomal degradation in both mouse and human cells. We also show that Smurf2 and RNF20 are colocalized at the γ-H2AX foci of double-stranded DNA breaks in the nucleus. Thus, Smurf2 has a tumor suppression function that normally maintains genomic stability by controlling the epigenetic landscape of histone modifications through RNF20.

• Publication year

  2011

• Venue

  Nature Medicine

• Publication date

  2011-11-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/nm.2596PMID 22231558PMCID 3274650
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Regulation of homologous recombination by RNF20-dependent H2B ubiquitination.

  2011cited by this paper
• Ablation of Smurf2 reveals an inhibition in TGF‐β signalling through multiple mono‐ubiquitination of Smad3

  2011cited by this paper
• Requirement of ATM-dependent monoubiquitylation of histone H2B for timely repair of DNA double-strand breaks.

  2011cited by this paper
• Smurf2 induces ubiquitin-dependent degradation of Smurf1 to prevent migration of breast cancer cells

  2010cited by this paper
• Histone H2B ubiquitylation disrupts local and higher order chromatin compaction

  2010cited by this paper
• Stress and the epigenetic landscape: a link to the pathobiology of human diseases?

  2010cited by this paper
• Smad ubiquitination regulatory factor 2 promotes metastasis of breast cancer cells by enhancing migration and invasiveness.

  2009cited by this paper
• RAD6-Mediated transcription-coupled H2B ubiquitylation directly stimulates H3K4 methylation in human cells.

  2009cited by this paper
• Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks

  2009cited by this paper
• Regulating the stability of TGFβ receptors and Smads

  2009cited by this paper
• Regulation of planar cell polarity by Smurf ubiquitin ligases.

  2009cited by this paper
• Chromatin structure influences the sensitivity of DNA to gamma-radiation.

  2008cited by this paper
• A Genecentric Human Protein Atlas for Expression Profiles Based on Antibodies*

  2008cited by this paper
• Smurf2 Induces Ubiquitin-dependent Degradation of Smurf1 to Prevent Migration of Breast Cancer Cells*

  2008cited by this paper
• Monoubiquitinated H2B is associated with the transcribed region of highly expressed genes in human cells

  2008cited by this paper
• Histone ubiquitination: triggering gene activity.

  2008cited by this paper
• γH2AX and cancer

  2008cited by this paper
• Retracted: Ubiquitination of the GTPase Rap1B by the ubiquitin ligase Smurf2 is required for the establishment of neuronal polarity

  2007cited by this paper
• Global chromatin compaction limits the strength of the DNA damage response

  2007cited by this paper
• Histone crosstalk between H2B monoubiquitination and H3 methylation mediated by COMPASS.

  2007cited by this paper
• Extraction, purification and analysis of histones

  2007cited by this paper
• Cellular response to etoposide treatment.

  2007cited by this paper
• Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway

  2006cited by this paper
• Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression.

  2006cited by this paper
• Clonogenic assay of cells in vitro

  2006cited by this paper
• Condensin I recruitment and uneven chromatin condensation precede mitotic cell death in response to DNA damage

  2006cited by this paper
• The human homolog of yeast BRE1 functions as a transcriptional coactivator through direct activator interactions.

  2005cited by this paper
• Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation.

  2005cited by this paper
• Micrococcal Nuclease Analysis of Chromatin Structure

  2005cited by this paper
• Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation.

  2005cited by this paper
• BUR kinase selectively regulates H3 K4 trimethylation and H2B ubiquitylation through recruitment of the PAF elongation complex.

  2005cited by this paper
• A Novel Domain in Set2 Mediates RNA Polymerase II Interaction and Couples Histone H3 K36 Methylation with Transcript Elongation

  2005cited by this paper
• Regulation of the TGFβ signalling pathway by ubiquitin-mediated degradation

  2004cited by this paper
• Smurf2 up-regulation activates telomere-dependent senescence.

  2004cited by this paper
• An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein

  2004cited by this paper
• High-level expression of the Smad ubiquitin ligase Smurf2 correlates with poor prognosis in patients with esophageal squamous cell carcinoma.

  2002cited by this paper
• Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast

  2002cited by this paper
• Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase.

  2001cited by this paper
• Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation.

  2000cited by this paper
• Smurf2 Is a Ubiquitin E3 Ligase Mediating Proteasome-dependent Degradation of Smad2 in Transforming Growth Factor-β Signaling* 210

  2000cited by this paper
• Determination of copy number of c-Myc protein per cell by quantitative Western blotting.

  1999cited by this paper
• Tumor surveillance via the ARF-p53 pathway.

  1998cited by this paper
• The ubiquitin system.

  1998cited by this paper
• Tumour-suppressor genes: evolving definitions in the genomic age

  1997cited by this paper
• p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts.

  1991cited by this paper
• A Laboratory manual

  1989cited by this paper
• Manipulating the mouse embryo: A laboratory manual

  1986cited by this paper
• QUANTITATIVE STUDIES OF THE GROWTH OF MOUSE EMBRYO CELLS IN CULTURE AND THEIR DEVELOPMENT INTO ESTABLISHED LINES

  1963cited by this paper

• SMURF2 attenuates NRF2-driven tumor progression by acting as a nuclear brake on NRF2 during cellular stress

  2026cites this paper
• In vivo CRISPR/Cas9 Screening Reveals that UBE2L3 Modulates Autophagic Flux through TSC2 Ubiquitination and Potentiates PD-1 Blockade in Triple-Negative Breast Cancer

  2026cites this paper
• SMURF2 in Anticancer Therapy: Dual Role in Carcinogenesis and Theranostics

  2026influential citation
• The role of HECT-type E3 ubiquitin ligases in DNA damage response and repair

  2025cites this paper
• Synthetic biology approaches to enhance cancer immune responses

  2025cites this paper
• Ubiquitin proteasome system (UPS): a crucial determinant of the epigenetic landscape in cancer.

  2025cites this paper
• Regulation of EZH2 protein stability: new mechanisms, roles in tumorigenesis, and roads to the clinic

  2024cites this paper
• Ubiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates

  2024cites this paper
• Targeting the SMURF2-HIF1α axis: a new frontier in cancer therapy

  2024cites this paper
• Citronellal improves endothelial dysfunction by affecting the stability of the GCH1 protein

  2024cites this paper
• Tumor‑suppressive effects of Smad‑ubiquitination regulator 2 in papillary thyroid carcinoma.

  2024cites this paper
• Quercetin‐induced degradation of RhoC suppresses hepatocellular carcinoma invasion and metastasis

  2024cites this paper
• Isoform alterations in the ubiquitination machinery impacting gastrointestinal malignancies

  2024cites this paper
• Smurf1 and Smurf2 mediated polyubiquitination and degradation of RNF220 suppresses Shh-group medulloblastoma

  2023cites this paper
• Loss of SMURF2 expression enhances RACK1 stability and promotes ovarian cancer progression

  2023cites this paper
• Regulatory role of E3 ubiquitin ligases in normal B lymphopoiesis and B-cell malignancies.

  2023cites this paper
• Intermediate, but not average: The unusual lives of the nuclear lamin proteins

  2023cites this paper
• HIF‐1α‐induced upregulated miR‐322 forms a feedback loop by targeting Smurf2 and Smad7 to activate Smad3/β‐catenin/HIF‐1α, thereby improving myocardial ischemia‐reperfusion injury

  2023cites this paper
• Exploiting the Endogenous Ubiquitin Proteasome System in Targeted Cancer Treatment

  2022influential citation
• Smurf2 regulates inflammation and collagen processing in cutaneous wound healing through TGF-β/Smad3 signaling.

  2022cites this paper
• The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response

  2022influential citation
• microRNA‐497‐mediated Smurf2/YY1/HIF2α axis in tumor growth and metastasis of esophageal squamous cell carcinoma

  2022cites this paper
• Smurf2 inhibition enhances chemotherapy and radiation sensitivity in non-small-cell lung cancer

  2022cites this paper
• The E3 ubiquitin ligase SMURF2 stabilizes RNA editase ADAR1p110 and promotes its adenosine-to-inosine (A-to-I) editing function

  2022cites this paper
• Mutated Tumor Suppressors Follow Oncogenes Profile by the Gene Hypermethylation of Partners in the Protein Interaction Networks

  2022cites this paper
• The Emerging Role of E3 Ubiquitin Ligase SMURF2 in the Regulation of Transcriptional Co-Repressor KAP1 in Untransformed and Cancer Cells and Tissues

  2022cites this paper
• SMURF2 phosphorylation at Thr249 modifies glioma stemness and tumorigenicity by regulating TGF-β receptor stability

  2022cites this paper
• Epigenetic reprogramming of human macrophages by an intestinal pathogen

  2021cites this paper
• [Phosphorylation of Smurf2 at Thr249 by Erk5 regulates TGF-β signaling].

  2021cites this paper
• Macroautophagy supports Sonic Hedgehog signaling by promoting Patched1 degradation.

  2021cites this paper
• SMURF2 phosphorylation at Thr249 modifies the stemness and tumorigenicity of glioma stem cells by regulating TGF-β receptor stability

  2021cites this paper
• The basics of molecular pathology

  2021cites this paper
• SMAD‐specific E3 ubiquitin ligase 2 promotes angiogenesis by facilitating PTX3 degradation in MSCs from patients with ankylosing spondylitis

  2021cites this paper
• SMURF2‐mediated ubiquitin signaling plays an essential role in the regulation of PARP1 PARylating activity, molecular interactions, and functions in mammalian cells

  2021cites this paper
• Posttranslational Modifications of Smurfs: Emerging Regulation in Cancer

  2021cites this paper
• Development and characterisation of SMURF2-targeting modifiers

  2021cites this paper
• Characterizing and exploiting the many roles of aberrant H2B monoubiquitination in cancer pathogenesis.

  2021cites this paper
• AAMP promotes colorectal cancermetastasis by suppressing SMURF2-mediatedubiquitination and degradation of RhoA

  2021cites this paper
• Mutant EGFR is a preferred SMURF2 substrate of ubiquitination: role in enhanced receptor stability and TKI sensitivity

  2020cites this paper
• SMURF2 prevents detrimental changes to chromatin, protecting human dermal fibroblasts from chromosomal instability and tumorigenesis

  2020influential citation
• Expression levels of SMAD specific E3 ubiquitin protein ligase 2 (Smurf2) and its interacting partners show region-specific alterations during brain aging.

  2020cites this paper
• Histone Monoubiquitination in Chromatin Remodelling: Focus on the Histone H2B Interactome and Cancer

  2020influential citation
• A novel negative regulatory mechanism of Smurf2 in BMP/Smad signaling in bone

  2020cites this paper
• SMURF1, a promoter of tumor cell progression?

  2020cites this paper
• ATXN7L3 positively regulates SMAD7 transcription in hepatocellular carcinoma with growth inhibitory function

  2020cites this paper
• Phosphorylation of SMURF2 by ATM exerts a negative feedback control of DNA damage response

  2020cites this paper
• Fragile Bones Secondary to SMURF1 Gene Duplication

  2020cites this paper
• HDAC3 Silencing Enhances Acute B Lymphoblastic Leukaemia Cells Sensitivity to MG-132 by Inhibiting the JAK/Signal Transducer and Activator of Transcription 3 Signaling Pathway

  2020cites this paper
• Ubiquitin ligase SMURF2 enhances epidermal growth factor receptor stability and tyrosine-kinase inhibitor resistance

  2020cites this paper
• Targeted Regulation of Nuclear Lamins by Ubiquitin and Ubiquitin-Like Modifiers

  2020cites this paper
• Ubiquitination-mediated degradation of SIRT1 by SMURF2 suppresses CRC cell proliferation and tumorigenesis

  2020cites this paper
• MiR‐195 and miR‐497 suppress tumorigenesis in lung cancer by inhibiting SMURF2‐induced TGF‐β receptor I ubiquitination

  2019cites this paper
• USF2 inhibits the transcriptional activity of Smurf1 and Smurf2 to promote breast cancer tumorigenesis.

  2019cites this paper
• Inhibition of Smurf2 translation by miR-322/503 protects from ischemia reperfusion injury by modulating EZH2/Akt/GSK3β signaling.

  2019cites this paper
• Reversible regulation of SATB1 ubiquitination by USP47 and SMURF2 mediates colon cancer cell proliferation and tumor progression.

  2019cites this paper
• The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B

  2019cites this paper
• MicroRNAs as Potential Targets for Therapeutic Intervention With Metastasis of Non-small Cell Lung Cancer

  2019cites this paper
• E3 ubiquitin ligases in B-cell malignancies.

  2019cites this paper
• E3 ubiquitin ligase Smurf2: a prognostic factor in microsatellite stable colorectal cancer

  2019cites this paper
• Altered Expression and Localization of Tumor Suppressive E3 Ubiquitin Ligase SMURF2 in Human Prostate and Breast Cancer

  2019cites this paper
• ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes

  2019cites this paper
• Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

  2019cites this paper
• The ubiquitination ligase SMURF2 reduces aerobic glycolysis and colorectal cancer cell proliferation by promoting ChREBP ubiquitination and degradation

  2019cites this paper
• RNF20 Functions as a Transcriptional Coactivator for PPARγ by Promoting NCoR1 Degradation in Adipocytes

  2019cites this paper
• HECT-Type E3 Ubiquitin Ligases in Cancer.

  2019cites this paper
• The role of E3 ubiquitin ligase HECTD3 in cancer and beyond

  2019cites this paper
• The functions and regulations of Smurfs in cancers.

  2019cites this paper
• Xist RNA antagonizes the SWI/SNF chromatin remodeler BRG1 on the inactive X chromosome

  2018cites this paper
• Somatic mutations in early onset luminal breast cancer

  2018cites this paper
• Smurf2 regulates stability and the autophagic–lysosomal turnover of lamin A and its disease‐associated form progerin

  2018influential citation
• Generation of Smurf2 Conditional Knockout Mice

  2018cites this paper
• Smurfs in Protein Homeostasis, Signaling, and Cancer

  2018influential citation
• Smurf2, an E3 ubiquitin ligase, interacts with PDE4B and attenuates liver fibrosis through miR-132 mediated CTGF inhibition.

  2018cites this paper
• A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples.

  2018cites this paper
• Spinal RNF20-Mediated Histone H2B Monoubiquitylation Regulates mGluR5 Transcription for Neuropathic Allodynia

  2018cites this paper
• کاهش بیان ژن Smurf2 Smad ubiquitin regulatory factor 2)) در بیماران مبتلا به RRMS و همراهی با افزایش میزان ناتوانی

  2018cites this paper
• WW-Domain Containing Protein Roles in Breast Tumorigenesis

  2018cites this paper
• Non-proteolytic ubiquitin modification of PPARγ by Smurf1 protects the liver from steatosis

  2018cites this paper
• let-7b and let-7c microRNAs promote histone H2B ubiquitylation and inhibit cell migration by targeting multiple components of the H2B deubiquitylation machinery

  2017cites this paper
• Ubiquitylation at the crossroads of development and disease

  2017cites this paper
• Microbial Signatures Associated with Oropharyngeal and Oral Squamous Cell Carcinomas

  2017cites this paper
• Generation of SMURF2 knockout human cells using the CRISPR/Cas9 system.

  2017cites this paper
• Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC

  2017cites this paper
• Lethal (3) malignant brain tumor-like 2 (L3MBTL2) protein protects against kidney injury by inhibiting the DNA damage-p53-apoptosis pathway in renal tubular cells.

  2017cites this paper
• Posttranscriptional regulation of intestinal epithelial integrity by noncoding RNAs

  2017cites this paper
• RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer

  2017cites this paper
• E3 ubiquitin ligases in cancer and implications for therapies

  2017cites this paper
• Smurf2-Mediated Stabilization of DNA Topoisomerase IIα Controls Genomic Integrity.

  2017cites this paper
• Exploring New Therapeutic Strategies for Osteoarthritis: From Genetic Manipulation of Skeletal Tissues to Chemically-modified Synthetic Hydrogels

  2017cites this paper
• Smurf1 targets Securin for ubiquitin-dependent degradation and regulates the metaphase-to-anaphase transition.

  2017cites this paper
• Skeletal Characterization of Smurf 2-Deficient Mice and In Vitro Analysis of Smurf 2-Deficient Chondrocytes

  2017cites this paper
• Challenges for Super-Resolution Localization Microscopy and Biomolecular Fluorescent Nano-Probing in Cancer Research

  2017cites this paper
• The PIAS3-Smurf2 sumoylation pathway suppresses breast cancer organoid invasiveness

  2017cites this paper
• The Drosophila F-box protein Slimb controls dSmurf protein turnover to regulate the Hippo pathway.

  2017cites this paper
• Smurf1 regulates lung cancer cell growth and migration through interaction with and ubiquitination of PIPKIγ

  2017cites this paper
• Diverse Functions and Signal Transduction of the Exocyst Complex in Tumor Cells

  2017influential citation
• Oncogenic Mutation of AIMP2/p38 Inhibits Its Tumor-Suppressive Interaction with Smurf2.

  2016cites this paper
• RING-, HECT-, and RBR-type E3 Ubiquitin Ligases: Involvement in Human Cancer.

  2016cites this paper
• Lenalidomide Stabilizes the Erythropoietin Receptor by Inhibiting the E3 Ubiquitin Ligase RNF41.

  2016cites this paper
• H2B ubiquitination regulates meiotic recombination by promoting chromatin relaxation

  2016cites this paper