SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases

Sun, Yilun; Nitiss, John L.; Pommier, ﻿Yves

doi:10.3389/fmolb.2022.871161

Cited by 11 publications

(10 citation statements)

References 140 publications

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“…After pretreatment with MG132, PFM03 or the combination, RH30 cells were treated with etoposide for 2 h, and the levels of covalent complexes were assessed by the ICE assay (Figures 6A-D). As previously shown, MG132 led to elevated levels of TOP2ccs upon etoposide treatment (Sun et al, 2022a). The level of TOP2ccs for both TOP2α and TOP2βccs upon treatment with etoposide and PFM03 was also elevated compared to etoposide alone.…”

Section: Combination Of Mre11 Inhibition and Proteasome Inhibition Do...supporting

confidence: 63%

Requirements for MRN endonuclease processing of topoisomerase II-mediated DNA damage in mammalian cells

Sun

Soans

Mishina

et al. 2022

Front. Mol. Biosci.

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During a normal topoisomerase II (TOP2) reaction, the enzyme forms a covalent enzyme DNA intermediate consisting of a 5′ phosphotyrosyl linkage between the enzyme and DNA. While the enzyme typically rejoins the transient breakage after strand passage, a variety of conditions including drugs targeting TOP2 can inhibit DNA resealing, leading to enzyme-mediated DNA damage. A critical aspect of the repair of TOP2-mediated damage is the removal of the TOP2 protein covalently bound to DNA. While proteolysis plays a role in repairing this damage, nucleolytic enzymes must remove the phosphotyrosyl-linked peptide bound to DNA. The MRN complex has been shown to participate in the removal of TOP2 protein from DNA following cellular treatment with TOP2 poisons. In this report we used an optimized ICE (In vivo Complex of Enzyme) assay to measure covalent TOP2/DNA complexes. In agreement with previous independent reports, we find that the absence or inhibition of the MRE11 endonuclease results in elevated levels of both TOP2α and TOP2β covalent complexes. We also examined levels of TOP2 covalent complexes in cells treated with the proteasome inhibitor MG132. Although MRE11 inhibition plus MG132 was not synergistic in etoposide-treated cells, ectopic overexpression of MRE11 resulted in removal of TOP2 even in the presence of MG132. We also found that VCP/p97 inhibition led to elevated TOP2 covalent complexes and prevented the removal of TOP2 covalent complexes by MRE11 overexpression. Our results demonstrate the existence of multiple pathways for proteolytic processing of TOP2 prior to nucleolytic processing, and that MRE11 can process TOP2 covalent complexes even when the proteasome is inhibited. The interactions between VCP/p97 and proteolytic processing of TOP2 covalent complexes merit additional investigation.

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Section: Combination Of Mre11 Inhibition and Proteasome Inhibition Do...supporting

confidence: 63%

Requirements for MRN endonuclease processing of topoisomerase II-mediated DNA damage in mammalian cells

Sun

Soans

Mishina

et al. 2022

Front. Mol. Biosci.

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“…5 In the past years, we focused on non-canonical protein PTMs that do not require writers (such as non-enzymatic glycation), [6][7][8][9] or in which the installation and removal are regulated by a single enzyme (such as monoaminylation). 10 Both of these two types of PTMs have been proven to serve as hallmarks in cancer cells, and thus the corresponding regulators (i.e., DJ-1/PARK7, 11 protein arginine deiminase 4, 12 and transglutaminase 2) 10 that are overexpressed in tumors may act as promising anti-cancer targets. 13 In our previous studies, we found that the fifth amino acid residue (glutamine) of H3 (H3Q5) was a major modification site of transglutaminase 2 (TGM2)-mediated dopaminylation in colorectal tumors.…”

Section: Introductionmentioning

confidence: 99%

Chemical proteomic profiling of protein dopaminylation in colorectal cancer cells

Zhang,

Gao,

Peng

et al. 2024

Preprint

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Histone dopaminylation is a newly identified epigenetic mark that plays a role in the regulation of gene transcription, where an isopeptide bond is formed between the fifth amino acid residue of H3 (i.e., glutamine) and dopamine. In our previous studies, we discovered that the dynamics of this post-translational modification (including installation, removal, and replacement) were regulated by a single enzyme, transglutaminase 2 (TGM2), through reversible transamination. Recently, we developed a chemical probe to specifically label and enrich histone dopaminylation via bioorthogonal chemistry. Given this powerful tool, we found that histone H3 glutamine 5 dopaminylation (H3Q5dop) was highly enriched in colorectal tumors, which could be attributed to the high expression level of TGM2 in colon cancer cells. Due to the enzyme promiscuity of TGM2, non-histone proteins have also been identified as targets of dopaminylation on glutamine residues, however, the dopaminylated proteome in cancer cells still remains elusive. Here, we utilized our chemical probe to enrich dopaminylated proteins from colorectal cancer cells in a bioorthogonal manner and performed the chemical proteomics analysis. Therefore, 425 dopaminylated proteins were identified, many of which are involved in nucleic acid metabolism and transcription pathways. More importantly, a number of modification sites of these dopaminylated proteins were identified, attributed to the successful application of our chemical probe. Overall, these findings shed light on the significant association between cellular protein dopaminylation and cancer development, further suggesting that to block the installation of protein dopaminylation may become a promising anti-cancer strategy.

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“…Human TOP2A gene encodes DNA topoisomerase IIα, which relieves topological DNA stress during gene transcription and regulates chromosome condensation and chromatid separation. TOP2A was reported as an indicator of proliferation rate in many human malignancies and to play important roles in maintaining genomic stability . In particular, SUMOylation of TOP2 is important during DNA repair by proteases and nucleases and for proper subnuclear localization and protein–protein interactions .…”

Section: Results and Discussionmentioning

confidence: 99%

“…TOP2A was reported as an indicator of proliferation rate in many human malignancies 40 and to play important roles in maintaining genomic stability. 41 In particular, SUMOylation of TOP2 is important during DNA repair by proteases and nucleases 42 and for proper subnuclear localization and protein–protein interactions. 43 Our proteomic analyses identified that all PIAS ligases SUMOylated Lys-1238, Lys-1240, and Lys-1370, potentially impacting protein stabilization, leading to an inhibition of p53 and increased cell proliferation.…”

Section: Results and Discussionmentioning

confidence: 99%

SUMO Proteomics Analyses Identify Protein Inhibitor of Activated STAT-Mediated Regulatory Networks Involved in Cell Cycle and Cell Proliferation

Boutet

Pascariu

et al. 2023

J. Proteome Res.

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Protein inhibitor of activated STAT (PIAS) proteins are E3 SUMO ligases playing important roles in protein stability and signaling transduction pathways. PIAS proteins are overexpressed in the triple-negative breast cancer cell line MDA-MB-231, and PIAS knockout (KO) results in a reduction in cell proliferation and cell arrest in the S phase. However, the molecular mechanisms underlying PIAS functions in cell proliferation and cell cycle remain largely unknown. Here, we used quantitative SUMO proteomics to explore the regulatory role of PIAS SUMO E3 ligases upon CRISPR/Cas9 KO of individual PIAS. A total of 1422 sites were identified, and around 10% of SUMO sites were regulated following KO of one or more PIAS genes. We identified protein substrates that were either specific to individual PIAS ligase or regulated by several PIAS ligases. Ki-67 and TOP2A, which are involved in cell proliferation and epithelial-to-mesenchymal transition, are SUMOylated at several lysine residues by all PIAS ligases, suggesting a level of redundancy between these proteins. Confocal microscopy and biochemical experiments revealed that SUMOylation regulated TOP2A protein stability, while this modification is involved in the recruitment of Ki-67 nucleolar proteins containing the SUMO interacting motif. These results provide novel insights into both the redundant and specific regulatory mechanisms of cell proliferation and cell cycle mediated by PIAS SUMO E3 ligases.

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SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases

Cited by 11 publications

References 140 publications

Requirements for MRN endonuclease processing of topoisomerase II-mediated DNA damage in mammalian cells

Requirements for MRN endonuclease processing of topoisomerase II-mediated DNA damage in mammalian cells

Chemical proteomic profiling of protein dopaminylation in colorectal cancer cells

SUMO Proteomics Analyses Identify Protein Inhibitor of Activated STAT-Mediated Regulatory Networks Involved in Cell Cycle and Cell Proliferation

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