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Centromere Binding and a Conserved Role in Chromosome Stability for SUMO-Dependent Ubiquitin Ligases  [PDF]
Loes A. L. van de Pasch, Antony J. Miles, Wilco Nijenhuis, Nathalie A. C. H. Brabers, Dik van Leenen, Philip Lijnzaad, Markus K. Brown, Jimmy Ouellet, Yves Barral, Geert J. P. L. Kops, Frank C. P. Holstege
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065628
Abstract: The Saccharomyces cerevisiae Slx5/8 complex is the founding member of a recently defined class of SUMO-targeted ubiquitin ligases (STUbLs). Slx5/8 has been implicated in genome stability and transcription, but the precise contribution is unclear. To characterise Slx5/8 function, we determined genome-wide changes in gene expression upon loss of either subunit. The majority of mRNA changes are part of a general stress response, also exhibited by mutants of other genome integrity pathways and therefore indicative of an indirect effect on transcription. Genome-wide binding analysis reveals a uniquely centromeric location for Slx5. Detailed phenotype analyses of slx5Δ and slx8Δ mutants show severe mitotic defects that include aneuploidy, spindle mispositioning, fish hooks and aberrant spindle kinetics. This is associated with accumulation of the PP2A regulatory subunit Rts1 at centromeres prior to entry into anaphase. Knockdown of the human STUbL orthologue RNF4 also results in chromosome segregation errors due to chromosome bridges. The study shows that STUbLs have a conserved role in maintenance of chromosome stability and links SUMO-dependent ubiquitination to a centromere-specific function during mitosis.
MMS21/HPY2 and SIZ1, Two Arabidopsis SUMO E3 Ligases, Have Distinct Functions in Development  [PDF]
Takashi Ishida, Mika Yoshimura, Kenji Miura, Keiko Sugimoto
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046897
Abstract: The small ubiquitin related modifier (SUMO)-mediated posttranslational protein modification is widely conserved among eukaryotes. Similar to ubiquitination, SUMO modifications are attached to the substrate protein through three reaction steps by the E1, E2 and E3 enzymes. To date, multiple families of SUMO E3 ligases have been reported in yeast and animals, but only two types of E3 ligases have been identified in Arabidopsis: SAP and Miz 1 (SIZ1) and Methyl Methanesulfonate-Sensitivity protein 21 (MMS21)/HIGH PLOIDY 2 (HPY2), hereafter referred to as HPY2. Both proteins possess characteristic motifs termed Siz/PIAS RING (SP-RING) domains, and these motifs are conserved throughout the plant kingdom. Previous studies have shown that loss-of-function mutations in HPY2 or SIZ1 cause dwarf phenotypes and that the phenotype of siz1-2 is caused by the accumulation of salicylic acid (SA). However, we demonstrate here that the phenotype of hpy2-1 does not depend on SA accumulation. Consistently, the expression of SIZ1 driven by the HPY2 promoter does not complement the hpy2-1 phenotypes, indicating that they are not functional homologs. Lastly, we show that the siz1-2 and hpy2-1 double mutant results in embryonic lethality, supporting the hypothesis that they have non-overlapping roles during embryogenesis. Together, these results suggest that SIZ1 and HPY2 function independently and that their combined SUMOylation is essential for plant development.
Concerted Action of the Ubiquitin-Fusion Degradation Protein 1 (Ufd1) and Sumo-Targeted Ubiquitin Ligases (STUbLs) in the DNA-Damage Response  [PDF]
Julie Bonne K?hler, Maria Louise M?nster J?rgensen, Gabriele Beinoraité, Michael Thorsen, Geneviève Thon
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080442
Abstract: In eukaryotes many players in the DNA-damage response (DDR) catalyze protein sumoylation or ubiquitylation. Emphasis has been placed on how these modifications orchestrate the sequential recruitment of repair factors to sites of DNA damage or stalled replication forks. Here, we shed light on a pathway in which sumoylated factors are eliminated through the coupled action of Sumo-targeted ubiquitin ligases (STUbLs) and the ubiquitin-fusion degradation protein 1 (Ufd1). Ufd1 is a subunit of the Cdc48-Ufd1-Npl4 complex implicated in the sorting of ubiquitylated substrates for degradation by the proteasome. We find that in fission yeast, Ufd1 interacts physically and functionally with the Sumo-targeted ubiquitin ligase (STUbL) Rfp1, homologous to human RNF4, and with the Sumo E3 ligase Pli1, homologous to human PIAS1. Deleting a C-terminal domain of Ufd1 that mediates the interaction of Ufd1 with Rfp1, Pli1, and Sumo (ufd1ΔCt213-342) lead to an accumulation of high-molecular-weight Sumo conjugates and caused severe genomic instabilities. The spectrum of sensitivity of ufd1ΔCt213-342 cells to genotoxins, the epistatic relationships of ufd1ΔCt213-342 with mutations in DNA repair factors, and the localization of the repair factor Rad22 in ufd1ΔCt213-342 cells point to ufd1ΔCt213-342 cells accumulating aberrant structures during replication that require homologous recombination (HR) for their repair. We present evidence that HR is however often not successful in ufd1ΔCt213-342 cells and we identify Rad22 as one of the high-molecular-weight conjugates accumulating in the ufd1ΔCt213-342 mutant consistent with Rad22 being a STUbL/Ufd1 substrate. Suggesting a direct role of Ufd1 in the processing of Sumo-conjugates, Ufd1 formed nuclear foci colocalizing with Sumo during the DDR, and Sumo-conjugates accumulated in foci in the ufd1ΔCt213-342 mutant. Broader functional relationships between Ufd1 and STUbLs conceivably affect numerous cellular processes beyond the DDR.
Comprehensive Identification of SUMO2/3 Targets and Their Dynamics during Mitosis  [PDF]
Julie Schou, Christian D. Kelstrup, Daniel G. Hayward, Jesper V. Olsen, Jakob Nilsson
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100692
Abstract: During mitosis large alterations in cellular structures occur rapidly, which to a large extent is regulated by post-translational modification of proteins. Modification of proteins with the small ubiquitin-related protein SUMO2/3 regulates mitotic progression, but few mitotic targets have been identified so far. To deepen our understanding of SUMO2/3 during this window of the cell cycle, we undertook a comprehensive proteomic characterization of SUMO2/3 modified proteins in mitosis and upon mitotic exit. We developed an efficient tandem affinity purification strategy of SUMO2/3 modified proteins from mitotic cells. Combining this purification strategy with cell synchronization procedures and quantitative mass spectrometry allowed for the mapping of numerous novel targets and their dynamics as cells progressed out of mitosis. This identified RhoGDIα as a major SUMO2/3 modified protein, specifically during mitosis, mediated by the SUMO ligases PIAS2 and PIAS3. Our data provide a rich resource for further exploring the role of SUMO2/3 modifications in mitosis and cell cycle regulation.
A Viral Ubiquitin Ligase Has Substrate Preferential SUMO Targeted Ubiquitin Ligase Activity that Counteracts Intrinsic Antiviral Defence  [PDF]
Chris Boutell ,Delphine Cuchet-Louren?o,Emilia Vanni,Anne Orr,Mandy Glass,Steven McFarlane,Roger D. Everett
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002245
Abstract: Intrinsic antiviral resistance represents the first line of intracellular defence against virus infection. During herpes simplex virus type-1 (HSV-1) infection this response can lead to the repression of viral gene expression but is counteracted by the viral ubiquitin ligase ICP0. Here we address the mechanisms by which ICP0 overcomes this antiviral response. We report that ICP0 induces the widespread proteasome-dependent degradation of SUMO-conjugated proteins during infection and has properties related to those of cellular SUMO-targeted ubiquitin ligases (STUbLs). Mutation of putative SUMO interaction motifs within ICP0 not only affects its ability to degrade SUMO conjugates, but also its capacity to stimulate HSV-1 lytic infection and reactivation from quiescence. We demonstrate that in the absence of this viral countermeasure the SUMO conjugation pathway plays an important role in mediating intrinsic antiviral resistance and the repression of HSV-1 infection. Using PML as a model substrate, we found that whilst ICP0 preferentially targets SUMO-modified isoforms of PML for degradation, it also induces the degradation of PML isoform I in a SUMO modification-independent manner. PML was degraded by ICP0 more rapidly than the bulk of SUMO-modified proteins in general, implying that the identity of a SUMO-modified protein, as well as the presence of SUMO modification, is involved in ICP0 targeting. We conclude that ICP0 has dual targeting mechanisms involving both SUMO- and substrate-dependent targeting specificities in order to counteract intrinsic antiviral resistance to HSV-1 infection.
Necdin Promotes Ubiquitin-Dependent Degradation of PIAS1 SUMO E3 Ligase  [PDF]
Ibrahim Gur, Kazushiro Fujiwara, Koichi Hasegawa, Kazuaki Yoshikawa
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099503
Abstract: Necdin, a pleiotropic protein that promotes differentiation and survival of mammalian neurons, is a member of MAGE (melanoma antigen) family proteins that share a highly conserved MAGE homology domain. Several MAGE proteins interact with ubiquitin E3 ligases and modulate their activities. However, it remains unknown whether MAGE family proteins interact with SUMO (small ubiquitin-like modifier) E3 ligases such as PIAS (protein inhibitor of activated STAT) family, Nsmce2/Mms21 and Cbx4/Pc2. In the present study, we examined whether necdin interacts with these SUMO E3 ligases. Co-immunoprecipitation analysis revealed that necdin, MAGED1, MAGEF1 and MAGEL2 bound to PIAS1 but not to Nsmce2 or Cbx4. These SUMO E3 ligases bound to MAGEA1 but failed to interact with necdin-like 2/MAGEG1. Necdin bound to PIAS1 central domains that are highly conserved among PIAS family proteins and suppressed PIAS1-dependent sumoylation of the substrates STAT1 and PML (promyelocytic leukemia protein). Remarkably, necdin promoted degradation of PIAS1 via the ubiquitin-proteasome pathway. In transfected HEK293A cells, amino- and carboxyl-terminally truncated mutants of PIAS1 bound to necdin but failed to undergo necdin-dependent ubiquitination. Both PIAS1 and necdin were associated with the nuclear matrix, where the PIAS1 terminal deletion mutants failed to localize, implying that the nuclear matrix is indispensable for necdin-dependent ubiquitination of PIAS1. Our data suggest that necdin suppresses PIAS1 both by inhibiting SUMO E3 ligase activity and by promoting ubiquitin-dependent degradation.
ATP-dependent DNA ligases
Ina V Martin, Stuart A MacNeill
Genome Biology , 2002, DOI: 10.1186/gb-2002-3-4-reviews3005
Abstract: DNA ligases are a large family of evolutionarily related proteins that play important roles in a wide range of DNA transactions, including chromosomal DNA replication, DNA repair and recombination, in all three kingdoms of life [1]. Cofactor preferences divide the ligases into two sub-families. Most eubacterial enzymes utilize NAD+ as a cofactor; these enzymes fall outside the scope of this article but have recently been reviewed elsewhere [2]. In contrast, most eukaryotic DNA ligases, together with archaeal and bacteriophage enzymes, fall into the second sub-family; these enzymes utilize ATP as a cofactor. Here we review the current state of knowledge of the cellular ATP-dependent DNA ligase enzymes in eukaryotic cells. Discussion of the function of related enzymes encoded by eukaryotic viruses can be found elsewhere [3].Vertebrate cells encode three well-characterized DNA ligases - DNA ligases I, III and IV - that appear to be descended from a common ancestral nucleotidyltransferase enzyme [4]. DNA ligase I is probably conserved in all eukaryotes: orthologs have been identified and characterized in organisms as diverse as yeast and mammals, and have been shown to play important roles in nuclear DNA replication, repair and recombination. In budding yeast a form of DNA ligase I also functions in mitochondrial DNA replication and repair, a role that in higher eukaryotes is taken by DNA ligase III. This latter enzyme, which to date has been identified only in vertebrates, is also present in the nucleus, where it functions in DNA repair and perhaps also in meiotic recombination. Like DNA ligase I, ligase IV is also likely to be conserved in all eukaryotes: to date, orthologs of DNA ligase IV have been identified and characterized in yeast, higher plants and vertebrates. These studies have identified a vital role for this enzyme in nuclear DNA repair.Consistent with their descent from a common ancestor, all the eukaryotic ATP-dependent DNA ligases are related in sequenc
Ubiquitin ligases and beyond
Ivan Dikic, Miranda Robertson
BMC Biology , 2012, DOI: 10.1186/1741-7007-10-22
Abstract: Pickart's article marked the expansion of ubiquitination from what most regarded as a niche preoccupation, with implications only for housekeeping protein turnover and the destruction of damaged ribosomal products, to seize the attention and excite the imagination of researchers in every area of cell biology. Comparisons to phosphorylation are rife - specific ubiquitin ligases promote ubiquitination and deubiquitinating enzymes terminate its effects of ubiquitination just as ubiquitination just as kinases and phosphatases induce and terminate the effects of phosphorylation - though ubiquitination, unlike phosphorylation, can operate irreversibly, by delivering its targets to the proteasome: hence its vital role in the progression of the cell cycle.It was already clear in 2004 that the number of ubiquitinating and deubiquitinating enzymes was very large, and that ubiquitin tags can be attached to proteins either as monomers or as poly-ubiquitin chains. But it had only recently been discovered that there are at least seven different kinds of poly-ubiquitin chains, and how the diversity of poly-ubiquitin signals is generated and interpreted in cells was in large part territory still to be explored.In a series of articles the first three of which are published this month, we review what is now known about some of the central issues in research on ubiquitination, revisiting the questions of how ubiquitin signals are conjugated to and removed from specific targets, and how they are recognized and contribute to the regulation of central processes in cells.Ubiquitin is a protein of 76 amino acids whose structure is shown in Figure 1. It is attached to a lysine in its target proteins either as a monomer or as a poly-ubiquitin chain each monomer of which is linked through its carboxy-terminal glycine to (usually) a lysine in the preceding ubiquitin in the chain. Three enzymes, known generically as E1, E2 and E3, act in series to catalyze ubiquitination (Figure 2). The E1 is t
To cooperate or to defect? Altruism and reputation  [PDF]
Krzysztof Kulakowski,Przemyslaw Gawronski
Physics , 2009, DOI: 10.1016/j.physa.2009.05.001
Abstract: The basic problem in the cooperation theory is to justify the cooperation. Here we propose a new approach, where players are driven by their altruism to cooperate or not. The probability of cooperation depends also on the co-player's reputation. We find that players with positive altruism cooperate and met cooperation. In this approach, payoffs are not relevant. The mechanism is most efficient in the fully connected network.
SUMO: regulating the regulator
Guillaume Bossis, Frauke Melchior
Cell Division , 2006, DOI: 10.1186/1747-1028-1-13
Abstract: Sumoylation, which consists in the covalent and reversible conjugation of Small Ubiquitin-related Modifiers (SUMO-1, 2 and 3 in mammals) to target proteins, is an essential cellular process from yeasts to mammals. In S. cerevisiae, disruption of the SUMO pathway leads to a G2/M cell cycle arrest [1]; In mouse, it leads to embryonic death at early stages [2].The number of known SUMO targets is growing exponentially, and it seems likely that this modification is as common as phosphorylation to regulate biological processes [3]. Most SUMO targets were initially found in the nucleus, but it is now clear that sumoylation also regulates cytoplasmic-, and even plasma membrane associated proteins. Modification has been linked to pathways as diverse as intracellular trafficking, cell cycle, DNA repair and replication, RNA metabolism and cell signalling (for detailed description of sumoylation functions see [4]). At a molecular level, sumoylation alters protein functions by masking and/or adding interaction surfaces, or by inducing conformational changes that result in altered interactions (for detailed examples see [5]). As a consequence, a wide variety of downstream consequences have been observed, including changes in localisation, enzymatic activity, or stability.Among the many known targets of sumoylation, a large number are regulators of gene expression, in particular transcription factors, co-activators or repressors. Here, the emerging picture is that sumoylation essentially results in down-regulation of gene expression. Albeit the molecular mechanisms underlying this repression by SUMO are still ill defined, they seem to involve SUMO-dependent recruitment of transcriptional repressors such as HDACs directly to promoters [6].All SUMO isoforms are conjugated via a conserved enzymatic cascade that resembles that of ubiquitin conjugation (Figure 1). SUMO is first activated by formation of a thioester bond between its C-terminal glycine and the catalytic cysteine of the h
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