Structure determination of the small ubiquitin-related modifier SUMO-1

Bayer, Peter; Arndt, Andreas; Metzger, Susanne; Mahajan, Rohit; Melchior, Frauke; Jaenicke, Rainer; Becker, Jörg

doi:10.1006/jmbi.1998.1839

Cited by 367 publications

(320 citation statements)

References 64 publications

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“…Th e results revealed that PTEN in both MD systems are stable and SUMO1 modifi cation is extended from PTEN in the system of SUMO1 -PTEN during the simulation time. One eminent feature of charge topology by analysis of the NMR structure of SUMO1 is a stable bipolar surface charge, which on one side displays a positively charged surface and on the other side exhibits a large negatively charged surface 27 . More recently, it has been reported SUMO1 can bind double-stranded DNA in a sequence-independent manner through electrostatic interaction between SUMO1-positive charge surface and acidic DNA 28 .…”

Section: Pten Sumoylation Suppresses Anchorage-independent Growthmentioning

confidence: 99%

SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane

et al. 2012

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The membrane association of the tumour suppressor phosphatase and tensin homologue (PTEN) is required to oppose the phosphatidylinositol-3-kinase / AKT pathway by dephosphorylation of phosphatidylinositol-3,4,5-triphosphate (PIP3). How cytosolic PTEN interacts with its main substrate, PIP3, localized at the inner face of plasma membrane remains unclear. Here we show that PTEN is covalently modifi ed by SUMO1 at both K 266 and K 254 sites in the C2 domain of PTEN. SUMO1 modifi cation at K 266 located in the CBR3 loop, which has a central role in PTEN membrane association, mainly facilitates cooperative binding of PTEN to the plasma membrane by electrostatic interactions. This results in the downregulation of the phosphatidylinositol-3 kinase / AKT pathway and consequently, suppression of anchorageindependent cell proliferation and tumour growth in vivo . Our data demonstrate a molecular mechanism whereby SUMO1 modifi cation is required for PTEN tumour suppressor function by controlling PTEN membrane association and regulation of the phosphatidylinositol-3 kinase / AKT pathway.

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Section: Pten Sumoylation Suppresses Anchorage-independent Growthmentioning

confidence: 99%

SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane

et al. 2012

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“…Each class employs a specific E2-E3 complex for target conjugation. SUMO is probably the most extensively characterized Ub-like molecule and its conjugation (sumoylation) often alters the target protein activity [21,22]. A triangle on the bottom template strand represents a replication block that stalls the replication machinery.…”

Section: Ubiquitination and Sumoylationmentioning

confidence: 99%

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Andersen¹,

Xiao³

2007

Cell Res

185

187

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npg In addition to well-defined DNA repair pathways, all living organisms have evolved mechanisms to avoid cell death caused by replication fork collapse at a site where replication is blocked due to disruptive covalent modifications of DNA. The term DNA damage tolerance (DDT) has been employed loosely to include a collection of mechanisms by which cells survive replication-blocking lesions with or without associated genomic instability. Recent genetic analyses indicate that DDT in eukaryotes, from yeast to human, consists of two parallel pathways with one being error-free and another highly mutagenic. Interestingly, in budding yeast, these two pathways are mediated by sequential modifications of the proliferating cell nuclear antigen (PCNA) by two ubiquitination complexes Rad6-Rad18 and Mms2-Ubc13-Rad5. Damage-induced monoubiquitination of PCNA by Rad6-Rad18 promotes translesion synthesis (TLS) with increased mutagenesis, while subsequent polyubiquitination of PCNA at the same K164 residue by Mms2-Ubc13-Rad5 promotes error-free lesion bypass. Data obtained from recent studies suggest that the above mechanisms are conserved in higher eukaryotes. In particular, mammals contain multiple specialized TLS polymerases. Defects in one of the TLS polymerases have been linked to genomic instability and cancer. DNA damage toleranceIn the presence of spontaneous or carcinogen-induced DNA damage, living cells have to maintain and complete DNA synthesis or risk replication fork collapse. Since the process of DNA licensing is to ensure the genome is duplicated once and only once during each cell cycle, stalled or collapsed replication forks may not be able to restart, which often results in double-strand breaks (DSBs) and causes compromised genome integrity or cell death. In addition to highly conserved DNA repair pathways, all living organisms have evolved schemes to ensure continuation of DNA synthesis in the presence of damage. These schemes were originally termed DNA postreplication repair (PRR) due to observations of transient shortened nascent DNA structures following S phase in response to DNA damage. In bacteria and unicellular yeast, these shortened DNA segments can be measured by an alkaline sedimentation assay [1] or directly observed in electron micrographs [2]. In wild-type cells, these truncated DNA segments were restored to full length following a short recovery time. One typical experiment [1] involved the restoration of the nascent strand following UV exposure in nucleotide excision repair (NER)-deficient cells and was originally assumed to represent a mechanism of DNA repair. However, further investigation revealed that, although the nascent fragments were re-annealed, the original UV-induced pyrimidine dimers, which were responsible for the generation of single-strand gaps, often persisted in the genome [3,4]. It was argued that the replication-blocking lesion was not necessarily corrected, but rather transiently bypassed and carried over to the next generation. Perhaps it is more beneficial for the organi...

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“…The most intensely studied human form of SUMO is the SUMO-1 protein, which is 48% identical to yeast Smt3 (Bayer et al, 1998;Mossessova and Lima, 2000). In vertebrates there are at least three additional proteins.…”

Section: Introductionmentioning

confidence: 99%

SUMO-1 Modification Alters ADAR1 Editing Activity

Desterro

Keegan

Jaffray

et al. 2005

MBoC

106

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We identify ADAR1, an RNA-editing enzyme with transient nucleolar localization, as a novel substrate for sumoylation. We show that ADAR1 colocalizes with SUMO-1 in a subnucleolar region that is distinct from the fibrillar center, the dense fibrillar component, and the granular component. Our results further show that human ADAR1 is modified by SUMO-1 on lysine residue 418. An arginine substitution of K418 abolishes SUMO-1 conjugation and although it does not interfere with ADAR1 proper localization, it stimulates the ability of the enzyme to edit RNA both in vivo and in vitro. Moreover, modification of wild-type recombinant ADAR1 by SUMO-1 reduces the editing activity of the enzyme in vitro. Taken together these data suggest a novel role for sumoylation in regulating RNA-editing activity. INTRODUCTIONA defining feature of eukaryotic cells is the generation of protein diversity either posttranscriptionally by alternative splicing and RNA editing or posttranslationally by modification of amino acids in proteins. One of the most recently discovered posttranslational modification mechanism in eukaryotes involves the covalent attachment of the small ubiquitinlike modifier, SUMO, to target proteins. Modification of proteins by SUMO, or sumoylation, plays crucial regulatory roles in eukaryotes. Proteins known to be modified by SUMO include, among others, RanGAP1, PCNA, I B␣, p53, c-jun, topoisomerases, promyelocytic leukemia protein (PML), Sp100, and the mitogen-activated protein kinase kinase 1 (MEKK1). Many SUMO substrates are transcription factors and cofactors, or proteins implicated in DNA repair and replication (reviewed by Hay, 2001;Melchior et al., 2003;Seeler and Dejean, 2003;Hay, 2005). Although it is well established that SUMO can affect target protein function by altering its subcellular localization, activity, or stability, for many substrates the biological functions of sumoylation remain unknown.Sumoylation is a reversible and highly dynamic process that involves formation of an isopeptide bond between the C-terminus of SUMO and the ⑀-amino group of a lysine residue of the target protein. The most intensely studied human form of SUMO is the SUMO-1 protein, which is 48% identical to yeast Smt3 (Bayer et al., 1998;Mossessova and Lima, 2000). In vertebrates there are at least three additional proteins. SUMO-2 and SUMO-3 are ϳ45% identical to SUMO-1 (Saitoh and Hinchey, 2000), and SUMO-4 shows an 86% amino acid homology to SUMO-2 (Bohren et al., 2004). SUMO is conjugated to protein substrates via an ATP-dependent enzymatic pathway that is mechanistically similar to ubiquitination. The reaction requires a SUMO protease that removes four amino acids from the C-terminus of the 101-amino acid SUMO-1 precursor to generate the mature form; an heterodimeric SUMO-activating enzyme, SAE1/2; Ubc9, a SUMO-conjugating enzyme that ligates directly to its protein target; and an E3-like SUMO ligase (reviewed Melchior et al., 2003). Three SUMO E3s have been identified so far: the mammalian protein inhibitors of activated S...

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Structure determination of the small ubiquitin-related modifier SUMO-1

Cited by 367 publications

References 64 publications

SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane

SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

SUMO-1 Modification Alters ADAR1 Editing Activity

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