The SUMO-specific isopeptidase SENP2 associates dynamically with nuclear pore complexes through interactions with karyopherins and the Nup107-160 nucleoporin subcomplex

Goeres, Jacqueline; Chan, Pak Kei; Mukhopadhyay, Debaditya; Zhang, Hong; Raught, Brian; Matunis, Michael J.

doi:10.1091/mbc.e10-12-0953

Cited by 57 publications

(74 citation statements)

References 56 publications

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“…4A). SENP1 was depleted by ϳ90%, whereas each of the three major isoforms of SENP2 recognized by our antibody (30) were depleted by ϳ70 -80%. Under these knockdown conditions, SENP1 depletion uniquely increased the ratio of SUMO-mod- ified to unmodified TDG.…”

Section: Resultsmentioning

confidence: 79%

Characterizing Requirements for Small Ubiquitin-like Modifier (SUMO) Modification and Binding on Base Excision Repair Activity of Thymine-DNA Glycosylase in Vivo

McLaughlin

Coey

Yang

et al. 2016

Journal of Biological Chemistry

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Thymine-DNA glycosylase (TDG) plays critical roles in DNA base excision repair and DNA demethylation. It has been proposed, based on structural studies and in vitro biochemistry, that sumoylation is required for efficient TDG enzymatic turnover following base excision. However, whether sumoylation is required for TDG activity in vivo has not previously been tested. We have developed an in vivo assay for TDG activity that takes advantage of its recently discovered role in DNA demethylation and selective recognition and repair of 5-carboxylcytosine. Using this assay, we investigated the role of sumoylation in regulating TDG activity through the use of TDG mutants defective for sumoylation and Small Ubiquitin-like Modifier (SUMO) binding and by altering TDG sumoylation through SUMO and SUMO protease overexpression experiments. Our findings indicate that sumoylation and SUMO binding are not essential for TDG-mediated excision and repair of 5-carboxylcytosine bases. Moreover, in vitro assays revealed that apurinic/apyrimidinic nuclease 1 provides nearly maximum stimulation of TDG processing of G⅐caC substrates. Thus, under our assay conditions, apurinic/apyrimidinic nuclease 1-mediated stimulation or other mechanisms sufficiently alleviate TDG product inhibition and promote its enzymatic turnover in vivo.Regulation and coordination of DNA repair mechanisms is essential for maintaining genome integrity and proper cell function. Sumoylation is a post-translational protein modification critical for DNA damage repair, including repair of DNA single-and double-stranded breaks, interstrand cross-links, and nucleotide mismatches (1, 2). Although affecting repair processes through a variety of distinct mechanisms, primary functions of sumoylation at DNA lesions include promotion of protein-protein interactions and stimulation of protein extraction or turnover (1, 3). The exact molecular effects of sumoylation on many modified repair factors, however, remain to be fully understood.Thymine-DNA glycosylase (TDG) 3 is a monofunctional glycosylase involved in DNA repair, DNA demethylation, and transcription activation (4 -6). The best studied role of TDG is in base excision repair (BER), where it specifically recognizes G/U and G/T mismatches arising from spontaneous deamination of cytosine or 5-methylcytosine, respectively. BER proceeds through a process involving glycosylase recognition of a specific DNA lesion and removal of the lesion to produce an apurinic/apyrimidinic (AP) site. TDG-mediated BER is of particular interest because of the observed product inhibition caused by high affinity binding of TDG to the AP site following base excision (7,8). This product inhibition can be relieved by apurinic/apyrimidinic endonuclease 1 (APE1), the enzyme that acts immediately downstream of TDG in the BER pathway (8, 9). Alternatively, in vitro studies and structural analyses have suggested an intriguing model for overcoming product inhibition involving TDG sumoylation (10 -14).TDG is sumoylated at a single lysine residue near its C te...

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Section: Resultsmentioning

confidence: 79%

Characterizing Requirements for Small Ubiquitin-like Modifier (SUMO) Modification and Binding on Base Excision Repair Activity of Thymine-DNA Glycosylase in Vivo

McLaughlin

Coey

Yang

et al. 2016

Journal of Biological Chemistry

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“…Interestingly, overexpression of SENP2 led to cell cycle arrest at the prometaphase stage, caused by defects in targeting the microtubule motor protein CENP-E to kinetochores [34]. Several studies showed that the N-terminal domains of SENP proteases determine their subcellular localization and interaction partners [35][36][37]. Indeed, a comparison between different chimeric fusion proteins of SENP1 and SENP2 revealed that the N-terminus of SENP2 is essential for its unique features.…”

Section: Redistribution Of the Sumo Machinery During Mitosismentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

243

211

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SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. KeywordsSUMO; mitosis; SUMOylation; cancer; cell cycle SUMO: a ubiquitin-like modifier that regulates nuclear processesThe complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of posttranslational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications such as phosphorylation [1], glycosylation [2] and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the activity, localization, half-life or interactome of the target protein. Since the initial discovery of ubiquitin, the founding member of these small protein posttranslational modifications in 1975 [4], a large family of structurally related ubiquitin-like modifiers has been uncovered including SUMO, Nedd8, ISG15, FAT10, FUB1, UFM1, URM1, Atg12 and Atg8 [5][6][7][8]. The attachment of these small ubiquitin-like modifiers is catalysed by an enzymatic cascade consisting of an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), and can be reversed by specific and cell cycle control. It is therefore not surprising that SUMO signal transduction has been implicated in the development of several different cancer types, which could potentially be exploited in anti-cancer therapies. In this review we will focus on the role of SUMO in cell cycle regulation, specifically highlighting its physiological relevance and its deregulation in cancer. Recent progress includes the identification of many novel SUMO substrates with important roles in cell cycle progression using proteomic approaches, and the demonstration that different mouse cancer models are dependent on a functioning SUMOylation system. Switching of SUMOylation in these cancer models caused a proliferation block of the cancer cells, showing that SUMO conjugating enzymes are potential drug targets. Europe PMC Funders Group Twenty years of SUMO research in cell cycle controlSUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO conjugating enzyme Ubc9 was first proposed to be a ubiquitin conjugating enzyme. Ubc9 was s...

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“…In most cell types, SENP1 is predominantly nuclear (e.g., Bailey and O'Hare 2004;Gong et al 2000;Itahana et al 2006). In contrast, SENP2, like yeast Ulp1, is associated with the nuclear face of the nuclear pore complex (Goeres et al 2011). Both SENP1 and SENP2 move between the nucleus and the cytoplasm (Goeres et al 2011;Kim et al 2005).…”

Section: Localisationmentioning

confidence: 99%

“…In contrast, SENP2, like yeast Ulp1, is associated with the nuclear face of the nuclear pore complex (Goeres et al 2011). Both SENP1 and SENP2 move between the nucleus and the cytoplasm (Goeres et al 2011;Kim et al 2005). This relocalisation is dependent on interactions with proteins associated with the nuclear pore complex as well as nuclear localisation sequences (NLSs) and nuclear export sequences (NESs) (Chow et al 2012;Goeres et al 2011;Itahana et al 2006;Kim et al 2005).…”

Section: Localisationmentioning

confidence: 99%

Starting and stopping SUMOylation

Watts

2013

Chromosoma

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A large number of proteins are modified posttranslationally by the ubiquitin-like protein (Ubl) SUMO. This process, known as sumoylation, regulates the function, localisation and activity of target proteins as part of normal cellular metabolism, e.g., during development, and through the cell cycle, as well as in response to a range of stresses. In order to be effective, the sumoylation pathway itself must also be regulated. This review describes how the SUMOylation process is regulated. In particular, regulation of the SUMO conjugation and deconjugation machinery at the level of transcription and by post-translational modifications is discussed.

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The SUMO-specific isopeptidase SENP2 associates dynamically with nuclear pore complexes through interactions with karyopherins and the Nup107-160 nucleoporin subcomplex

Cited by 57 publications

References 56 publications

Characterizing Requirements for Small Ubiquitin-like Modifier (SUMO) Modification and Binding on Base Excision Repair Activity of Thymine-DNA Glycosylase in Vivo

Characterizing Requirements for Small Ubiquitin-like Modifier (SUMO) Modification and Binding on Base Excision Repair Activity of Thymine-DNA Glycosylase in Vivo

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Starting and stopping SUMOylation

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