PIASy Mediates SUMO-2/3 Conjugation of Poly(ADP-ribose) Polymerase 1 (PARP1) on Mitotic Chromosomes

Ryu, Hyunju; Al-Ani, Gada; Deckert, Katelyn; Kirkpatrick, Donald S.; Gygi, Steven P.; Dasso, Mary; Azuma, Yoshiaki

doi:10.1074/jbc.m109.074583

Cited by 50 publications

(74 citation statements)

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“…SUMOylation of PARP-1, however, did not alter the activity or localization of the enzyme. Still, inhibition of the SUMO pathway strongly increases PARylation at mitotic chromosomes, demonstrating that these two posttranslational modifications harbour interconnected roles during chromosomal segregation [110].…”

Section: Text Box 1 Sumoylation Regulates Topoisomerase Iiα In Mitosismentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

246

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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Section: Text Box 1 Sumoylation Regulates Topoisomerase Iiα In Mitosismentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

246

211

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“…46 SUMOylation appears to be important for remodeling of attachments of Topoisomerase II to chromatin 43 and for negative regulation of PARP1 activity against chromosomal substrates. 45 The biological role of Borealin SUMOylation is not clear. 46 Outer kinetochore and fibrous corona proteins that are confirmed SUMOylation targets include BubR1 (a SAC component), Nuf2 (a member of the Hec1 MT binding complex) and CENP-E (a plus end-directed MT motor) ( Table 1).…”

Section: Mukhopadhyay* and Mary Dassomentioning

confidence: 99%

“…Experiments in mitotic Xenopus egg extracts (XEEs) using GFP-SUMO-2/3 demonstrate considerable accumulation of SUMO-2/3 in the ICR region. 43 ICR components that are confirmed SUMOylation targets include Topoisomerase II, 44 poly(ADP-ribose) polymerase 1 (PARP1) 45 and the chromosome passenger complex component Borealin. 46 SUMOylation appears to be important for remodeling of attachments of Topoisomerase II to chromatin 43 and for negative regulation of PARP1 activity against chromosomal substrates.…”

Section: Mukhopadhyay* and Mary Dassomentioning

confidence: 99%

The fate of metaphase kinetochores is weighed in the balance of SUMOylation during S phase

Mukhopadhyay¹,

Dasso

2010

Cell Cycle

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G enetic evidence suggests that conjugation of Small Ubiquitin-likeModifier proteins (SUMOs) plays an important role in kinetochore function, although the mechanism underlying these observations are poorly defined. We found that depletion of the SUMO protease SENP6 from HeLa cells causes chromosome misalignment, prolonged mitotic arrest and chromosome missegregation. Many inner kinetochore proteins (IKPs) were mis-localized in SENP6-depleted cells. This gross mislocalization of IKPs is due to proteolytic degradation of CENP-I and CENP-H via the SUMO targeted Ubiquitin Ligase (STUbL) pathway. Our findings show that SENP6 is a key regulator of inner kinetochore assembly that antagonizes the cellular STUbL pathway to protect IKPs from degradation during S phase. Here, we will briefly review the implications of our findings and present new data on how SUMOylation during S phase can control chromosome alignment in the subsequent metaphase.

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“…SUMO is conjugated to cellular substrates by an analogous pathway to that of ubiquitin. It has been reported that SUMOylation is mediated without E3 ligases in vitro (5,6), but under physiological conditions, SUMO E3 ligases are essential to execute SUMOylation of cellular substrates (7)(8)(9)(10). There are mainly two types of SUMO E3 ligases in vertebrates, RanBP2 (Nup358), and Siz/PIAS.…”

mentioning

confidence: 99%

“…For example, DNA topoisomerase II␣ (TopoII␣) and poly [ADP-ribose] polymerase I (PARP1) are each modified by SUMO2/3 in a PIASy-dependent manner during mitosis (9,20). Immunodepletion of PIASy completely abolishes mitotic chromosomal SUMOylation in Xenopus egg extracts (XEE) and other PIAS family proteins fail to restore this defect, indicating a unique role of PIASy in mitotic chromosomal SUMOylation in XEE (7).…”

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confidence: 99%

Rod/Zw10 Complex Is Required for PIASy-dependent Centromeric SUMOylation

Ryu

Azuma

2010

Journal of Biological Chemistry

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SUMO conjugation of cellular proteins is essential for proper progression of mitosis. PIASy, a SUMO E3 ligase, is required for mitotic SUMOylation of chromosomal proteins, yet the regulatory mechanism behind the PIASy-dependent SUMOylation during mitosis has not been determined. Using a series of truncated PIASy proteins, we have found that the N terminus of PIASy is not required for SUMO modification in vitro but is essential for mitotic SUMOylation in Xenopus egg extracts. We demonstrate that swapping the N terminus of PIASy protein with the corresponding region of other PIAS family members abolishes chromosomal binding and mitotic SUMOylation. We further show that the N-terminal domain of PIASy is sufficient for centromeric localization. We identified that the N-terminal domain of PIASy interacts with the Rod/Zw10 complex, and immunofluorescence further reveals that PIASy colocalizes with Rod/Zw10 in the centromeric region. We show that the Rod/Zw10 complex interacts with the first 47 residues of PIASy which were particularly important for mitotic SUMOylation. Finally, we show that depletion of Rod compromises the centromeric localization of PIASy and SUMO2/3 in mitosis. Together, we demonstrate a fundamental mechanism of PIASy to localize in the centromeric region of chromosome to execute centromeric SUMOylation during mitosis.SUMOylation is a protein modification process conserved from yeast to vertebrates (1). The consequences of SUMO 2 (small ubiquitin-like modifier) modification that have been elucidated over the past decade include modulation of gene transcription, DNA repair, protein translocation, protein/protein interaction, chromosomal organization, and sister chromatid segregation (2-4). Vertebrates have three SUMO isoforms and all three display roughly 50% identity with the single SUMO found in yeast (1). SUMO is conjugated to cellular substrates by an analogous pathway to that of ubiquitin. It has been reported that SUMOylation is mediated without E3 ligases in vitro (5, 6), but under physiological conditions, SUMO E3 ligases are essential to execute SUMOylation of cellular substrates (7-10). There are mainly two types of SUMO E3 ligases in vertebrates, RanBP2 (Nup358), and Siz/PIAS. RanBP2 has no homolog in yeast, and its ligase function is independent of either HECT or Ring finger-type ubiquitin E3 ligases (11). Siz/PIAS, on the other hand, initially identified in budding yeast, functions similar to Ring finger ubiquitin ligases (8). Vertebrates have four PIAS proteins (PIAS1, PIAS3, PIASx, and PIASy) that share important conserved functional domains (12). The SAP (scaffold attachment factor-A/B, acinus and PIAS) domain is positioned at the N terminus, and directly binds AT-rich regions of DNA (13-15). The SP-Ring domain is related to that of ubiquitin E3 ligase and is responsible for Ubc9 recruitment (16). The SUMO-interacting motif (SIM) is situated after the SP-Ring and redirects the Ubc9ϳSUMO complex on substrate proteins, potentially contributing to SUMO paralogue specificity (17,18). Doma...

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PIASy Mediates SUMO-2/3 Conjugation of Poly(ADP-ribose) Polymerase 1 (PARP1) on Mitotic Chromosomes

Cited by 50 publications

References 35 publications

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

The fate of metaphase kinetochores is weighed in the balance of SUMOylation during S phase

Rod/Zw10 Complex Is Required for PIASy-dependent Centromeric SUMOylation

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