SUMO, a small, but powerful, regulator of double-strand break repair

Garvin, Alexander J; Morris, Joanna R.

doi:10.1098/rstb.2016.0281

Cited by 69 publications

(73 citation statements)

References 171 publications

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“…Emerging evidences revealed that small ubiquitin‐like modifiers (SUMOs) such as SUMO‐1, SUMO‐2, and SUMO‐3 in mammalian systems are found covalently attached to more than 50 proteins including p53, androgen receptor, IkBα, c‐jun, histone deacetylases (HDACs), and other proteins with major functions of SUMOylation, cytoplasmic nuclear transport, transcripton, and DNA repair …”

Section: Introductionmentioning

confidence: 99%

Melatonin disturbs SUMOylation‐mediated crosstalk between c‐Myc and nestin via MT1 activation and promotes the sensitivity of paclitaxel in brain cancer stem cells

Lee

Jung

Shin

et al. 2018

Journal of Pineal Research

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Here the underlying antitumor mechanism of melatonin and its potency as a sensitizer of paclitaxel was investigated in X02 cancer stem cells. Melatonin suppressed sphere formation and induced G2/M arrest in X02 cells expressing nestin, CD133, CXCR4, and SOX-2 as biomarkers of stemness. Furthermore, melatonin reduced the expression of CDK2, CDK4, cyclin D1, cyclin E, and c-Myc and upregulated cyclin B1 in X02 cells. Notably, genes of c-Myc related mRNAs were differentially expressed in melatonin-treated X02 cells by microarray analysis. Consistently, melatonin reduced the expression of c-Myc at mRNA and protein levels, which was blocked by MG132. Of note, overexpression of c-Myc increased the expression of nestin, while overexpression of nestin enhanced c-Myc through crosstalk despite different locations, nucleus, and cytoplasm. Interestingly, melatonin attenuated small ubiquitin-related modifier-1 (SUMO-1) more than SUMO-2 or SUMO-3 and disturbed nuclear translocation of nestin for direct binding to c-Myc by SUMOylation of SUMO-1 protein by immunofluorescence and immunoprecipitation. Also, melatonin reduced trimethylated histone H3K4me3 and H3K36me3 more than dimethylation in X02 cells by Western blotting and chromatin immunoprecipitation assay. Notably, melatonin upregulated MT1, not MT2, in X02 cells and melatonin receptor inhibitor luzindole blocked the ability of melatonin to decrease the expression of nestin, p-c-Myc(S62), and c-Myc. Furthermore, melatonin promoted cytotoxicity, sub-G1 accumulation, and apoptotic body formation by Paclitaxcel in X02 cells. Taken together, these findings suggest that melatonin inhibits stemness via suppression of c-Myc, nestin, and histone methylation via MT1 activation and promotes anticancer effect of Paclitaxcel in brain cancer stem cells.

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Section: Introductionmentioning

confidence: 99%

Melatonin disturbs SUMOylation‐mediated crosstalk between c‐Myc and nestin via MT1 activation and promotes the sensitivity of paclitaxel in brain cancer stem cells

Lee

Jung

Shin

et al. 2018

Journal of Pineal Research

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“…Other aspects of sumoylation, such as protein conformational changes, are not mimicked by our SIM recruitment approach and may be important for recruiting DNA repair factors. In addition to telomere binding proteins, many DNA repair factors are also sumoylated including 53BP1 and PCNA (Garvin and Morris, 2017). Sumoylation of those DNA repair factors, not captured in our dimerization approach, may be required for recruitment to APBs.…”

Section: Discussionmentioning

confidence: 99%

Liquid condensation drives telomere clustering during ALT

Liu

Dilley

Chenoweth

et al. 2019

Preprint

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17Telomerase-free cancer cells employ a recombination-based alternative lengthening of 18 telomeres (ALT) pathway that depends on ALT-associated promyelocytic leukemia 19 (PML) nuclear bodies (APBs), whose function is unclear. We find that APBs behave as 20 liquid condensates, suggesting two potential mechanisms to promote telomere 21 elongation: condensation to enrich DNA repair factors for telomere synthesis and 22 coalescence to cluster telomeres to provide repair templates. Using chemically-induced 23 dimerization, we show that telomere sumoylation nucleates APB condensation via 24 SUMO-SIM (SUMO interaction motif) interactions and clusters telomeres. The induced 25 APBs lack DNA repair factors, indicating that these factors are clients recruited to the 26 APB scaffold rather than components that drive condensation. Telomere clustering, 27 however, relies only on liquid properties of the condensate, as an alternative 28 condensation chemistry also induces clustering. Our results demonstrate how the 29 material properties and chemical composition of APBs independently contribute to ALT, 30 suggesting a general framework for how liquid condensates promote cellular functions. 31 32 42 presence of APBs, a class of ALT telomere-associated promyelocytic leukemia (PML) 43 nuclear bodies used for ALT diagnosis (Yeager et al., 1999). PML nuclear bodies are 44 3 dynamic structures in the nucleus that transiently sequester up to 100 different proteins 45 that are implicated in many cellular functions including tumor suppression, DNA 46 replication, gene transcription, DNA repair, viral pathogenicity, cellular senescence and 47 apoptosis (Lallemand-Breitenbach and de The, 2010). While APBs are proposed to be 48 sites of telomere recombination during ALT, the precise functions of these specialized 49 PML nuclear bodies are poorly understood. Inhibiting APB formation by knocking down 50 PML protein, an essential component of PML nuclear bodies, leads to telomere 51shortening (Draskovic et al., 2009; Osterwald et al., 2015), indicating that APBs are 52 essential for ALT telomere maintenance. In addition to typical PML nuclear body 53 components, APBs contain proteins involved in homologous recombination such as 54 replication protein A (RPA), Rad51, and breast cancer susceptibility protein 1 (BRCA1) 55 (Nabetani and Ishikawa, 2011), which suggests that APBs promote telomere synthesis. 56Indeed, new telomere DNA synthesis has been detected in APBs (Cho et al., 2014; 57 Chung et al., 2011; O'sullivan et al., 2014; Sahin et al., 2014; Zhang et al., 2019). 58Telomeres also cluster within APBs, as another unique feature of ALT, presumably to 59 provide repair templates for telomere DNA synthesis. Many functionally distinct proteins 60 can initiate APB assembly, leading to the proposal of a multiple-pathway model (Chung 61 et al., 2011), as suggested by an RNA interference screen that identified close to thirty 62 proteins that affect APB formation, including proteins involved in telomere and 63 chromatin organizatio...

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“…In particular, many proteins involved in gene expression (transcription factors, transcription machinery, co-regulators, histones) are regulated by their SUMOylation (Neyret-Kahn et al, 2013;Cossec et al, 2018;Rosonina et al, 2017;Tempé et al, 2014;Chymkowitch et al, 2015). SUMOylation also plays key roles in DNA damage repair through the modification of many proteins involved in this process (Garvin & Morris, 2017).…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin and SUMO conjugation as biomarkers of Acute Myeloid Leukemias response to chemotherapies

Gâtel

Brockly

Reynès

et al. 2019

Preprint

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AbstractUbiquitin and the ubiquitin-like SUMO are covalently conjugated to thousands of proteins to modulate their function and fate. Many of the enzymes involved in their conjugation are dysregulated in cancers and involved in cancer cells response to therapies. We describe here the identification of biomarkers of the activity of these enzymes and their use to predict Acute Myeloid Leukemias (AML) response to standard chemotherapy (daunorubicine-DNR and cytarabine-Ara-C). We compared the ability of extracts from chemosensitive and chemoresistant AML cells to conjugate ubiquitin or SUMO-1 on 9000 proteins spotted on protein-arrays. We identified 122 proteins whose conjugation by these post-translational modifiers marks AML resistance to DNR and/or Ara-C. Based on this modifomic signature, we defined a statistical score able to predict AML patient response to standard chemotherapy. We finally developed a miniaturized assay to easily assess the modification level of the selected biomarkers and validated it in patient cell extracts. Thus, our work identifies a new type of ubiquitin-based biomarkers that could be used to predict cancer patients response to treatments.Summary blurbThis study describes the identification of a new class of biomarkers of cancer response to therapies based on protein modification by Ubiquitin and SUMO and provides the tools to analyze them in Acute Myeloid Leukemia patient samples.

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SUMO, a small, but powerful, regulator of double-strand break repair

Cited by 69 publications

References 171 publications

Melatonin disturbs SUMOylation‐mediated crosstalk between c‐Myc and nestin via MT1 activation and promotes the sensitivity of paclitaxel in brain cancer stem cells

Melatonin disturbs SUMOylation‐mediated crosstalk between c‐Myc and nestin via MT1 activation and promotes the sensitivity of paclitaxel in brain cancer stem cells

Liquid condensation drives telomere clustering during ALT

Ubiquitin and SUMO conjugation as biomarkers of Acute Myeloid Leukemias response to chemotherapies

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