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  • 1
    Language: English
    In: The EMBO journal, 2007-09-19, Vol.26 (18), p.4089-4101
    Description: We identify the SUMO‐Targeted Ubiquitin Ligase (STUbL) family of proteins and propose that STUbLs selectively ubiquitinate sumoylated proteins and proteins that contain SUMO‐like domains (SLDs). STUbL recruitment to sumoylated/SLD proteins is mediated by tandem SUMO interaction motifs (SIMs) within the STUbLs N‐terminus. STUbL‐mediated ubiquitination maintains sumoylation pathway homeostasis by promoting target protein desumoylation and/or degradation. Thus, STUbLs establish a novel mode of communication between the sumoylation and ubiquitination pathways. STUbLs are evolutionarily conserved and include: Schizosaccharomyces pombe Slx8‐Rfp (founding member), Homo sapiens RNF4, Dictyostelium discoideum MIP1 and Saccharomyces cerevisiae Slx5–Slx8. Cells lacking Slx8‐Rfp accumulate sumoylated proteins, display genomic instability, and are hypersensitive to genotoxic stress. These phenotypes are suppressed by deletion of the major SUMO ligase Pli1, demonstrating the specificity of STUbLs as regulators of sumoylated proteins. Notably, human RNF4 expression restores SUMO pathway homeostasis in fission yeast lacking Slx8‐Rfp, underscoring the evolutionary functional conservation of STUbLs. The DNA repair factor Rad60 and its human homolog NIP45, which contain SLDs, are candidate STUbL targets. Consistently, Rad60 and Slx8‐Rfp mutants have similar DNA repair defects.
    Subject(s): Adaptation, Physiological - drug effects ; Amino Acid Motifs ; Amino Acid Sequence ; Cellular biology ; Conserved Sequence ; desumoylation ; Dictyostelium discoideum ; DNA Damage ; DNA repair ; DNA Repair - drug effects ; DNA Replication - drug effects ; Evolution, Molecular ; Gene Deletion ; Genomic Instability - drug effects ; Genomics ; Homeostasis - drug effects ; Humans ; Microbial Viability - drug effects ; Models, Biological ; Molecular biology ; Molecular Sequence Data ; Mutagens - pharmacology ; Phenotype ; Protein Binding - drug effects ; Proteins ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae - cytology ; Saccharomyces cerevisiae - drug effects ; Saccharomyces cerevisiae - enzymology ; Schizosaccharomyces - drug effects ; Schizosaccharomyces - enzymology ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe ; Schizosaccharomyces pombe Proteins - chemistry ; Sequence Homology, Amino Acid ; Signal transduction ; Small Ubiquitin-Related Modifier Proteins - metabolism ; STUbL ; SUMO ; ubiquitin ligase ; Ubiquitin-Conjugating Enzymes - metabolism
    ISSN: 0261-4189
    E-ISSN: 1460-2075
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: Get It Now
    Source: Wiley-Blackwell Full Collection 2014
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  • 2
    Language: English
    In: EMBO reports, 2014-05, Vol.15 (5), p.601-608
    Description: The post‐translational modification of DNA repair and checkpoint proteins by ubiquitin and small ubiquitin‐like modifier (SUMO) critically orchestrates the DNA damage response (DDR). The ubiquitin ligase RNF4 integrates signaling by SUMO and ubiquitin, through its selective recognition and ubiquitination of SUMO‐modified proteins. Here, we define a key new determinant for target discrimination by RNF4, in addition to interaction with SUMO. We identify a nucleosome‐targeting motif within the RNF4 RING domain that can bind DNA and thereby enables RNF4 to selectively ubiquitinate nucleosomal histones. Furthermore, RNF4 nucleosome‐targeting is crucially required for the repair of TRF2‐depleted dysfunctional telomeres by 53BP1‐mediated non‐homologous end joining. Synopsis RNF4 is an important ubiquitin ligase in the DNA damage response (DDR) that targets SUMOylated proteins. This study shows that it also contains a nucleosome‐targeting motif that crucially supports the DDR genome‐wide. RNF4 promotes ATM‐dependent 53BP1 recruitment and repair at dysfunctional telomeres. RNF4 RING domain contains an RNF168 and RING1b‐related nucleosome‐targeting motif. RNF4 recognizes both SUMO and nucleosomes to support DNA repair . RNF4 is an important ubiquitin ligase in the DNA damage response (DDR) that targets SUMOylated proteins. This study shows that it also contains a nucleosome‐targeting motif that crucially supports the DDR genome‐wide.
    Subject(s): Amino Acid Motifs ; Animals ; Cell Line ; Chromosomal Proteins, Non-Histone - metabolism ; Crystallography, X-Ray ; Deoxyribonucleic acid ; DNA ; DNA Damage ; DNA Repair ; DNA-Binding Proteins - metabolism ; Gene Knockout Techniques ; Mice ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Nuclear Proteins - ultrastructure ; Nucleosomes - metabolism ; Protein Processing, Post-Translational ; Protein Structure, Tertiary ; Proteins ; RNF4 ; Scientific Reports ; small ubiquitin-like modifier ; Small Ubiquitin-Related Modifier Proteins - metabolism ; SUMO-targeted E3 ubiquitin ligase (STUbL) ; Tamoxifen - analogs & derivatives ; Tamoxifen - pharmacology ; telomere ; Telomere - drug effects ; Telomere - genetics ; Telomeric Repeat Binding Protein 2 - genetics ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcription Factors - ultrastructure ; Tumor Suppressor p53-Binding Protein 1 ; ubiquitin ; Ubiquitin - metabolism ; Ubiquitination
    ISSN: 1469-221X
    E-ISSN: 1469-3178
    Source: HighWire Press (Free Journals)
    Source: Wiley Online Library All Journals
    Source: PubMed Central
    Source: Get It Now
    Source: Wiley-Blackwell Full Collection 2014
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  • 3
    Language: English
    In: The Journal of biological chemistry, 2012-08-24, Vol.287 (35), p.29610-29619
    Description: Protein modification by SUMO and ubiquitin critically impacts genome stability via effectors that “read” their signals using SUMO interaction motifs or ubiquitin binding domains, respectively. A novel mixed SUMO and ubiquitin signal is generated by the SUMO-targeted ubiquitin ligase (STUbL), which ubiquitylates SUMO conjugates. Herein, we determine that the “ubiquitin-selective” segregase Cdc48-Ufd1-Npl4 also binds SUMO via a SUMO interaction motif in Ufd1 and can thus act as a selective receptor for STUbL targets. Indeed, we define key cooperative DNA repair functions for Cdc48-Ufd1-Npl4 and STUbL, thereby revealing a new signaling mechanism involving dual recruitment by SUMO and ubiquitin for Cdc48-Ufd1-Npl4 functions in maintaining genome stability. Background: SUMO-targeted ubiquitylation controls critical cellular processes, including genome stability; but effectors and mechanisms remain undefined. Results: The Cdc48-Ufd1-Npl4 segregase binds SUMO and cooperates with the SUMO-targeted ubiquitin ligase (STUbL) in DNA repair. Conclusion: Cdc48-Ufd1-Npl4 acts as a STUbL effector. Significance: Novel dual recognition of SUMO and ubiquitin co-modified proteins likely provides selectivity and specificity in signaling by these critical factors.
    Subject(s): Adenosine Triphosphatases - genetics ; Adenosine Triphosphatases - metabolism ; Amino Acid Motifs ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cdc48-Ufd1-Npl4 ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; DNA Repair ; DNA Repair - physiology ; DNA Topoisomerase ; DNA, Fungal - genetics ; DNA, Fungal - metabolism ; Genomic Instability - physiology ; p97 ; Protein Binding ; RNF4 ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - metabolism ; Signal Transduction ; Signal Transduction - physiology ; STUbL ; Sumo ; SUMO-1 Protein - genetics ; SUMO-1 Protein - metabolism ; Top1 ; Ubiquitin ; Ubiquitin - genetics ; Ubiquitin - metabolism ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination - physiology ; Valosin Containing Protein
    ISSN: 0021-9258
    E-ISSN: 1083-351X
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: Molecular and Cellular Biology, 2012-01-15, Vol.32 (2), p.276-287
    Description: Article Usage Stats Services MCB Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue MCB About MCB Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy MCB RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0270-7306 Online ISSN: 1098-5549 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to MCB .asm.org, visit: MCB       
    Subject(s): Amino Acid Motifs ; Cisplatin - pharmacology ; Cross-Linking Reagents - pharmacology ; DNA Helicases - genetics ; DNA Helicases - metabolism ; DNA Repair ; DNA, Fungal - metabolism ; Gene Expression Regulation, Fungal ; Genes, Fungal ; Genomic Instability - drug effects ; Mutation ; RecQ Helicases - chemistry ; RecQ Helicases - genetics ; RecQ Helicases - metabolism ; Schizosaccharomyces - chemistry ; Schizosaccharomyces - drug effects ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - chemistry ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - metabolism
    ISSN: 0270-7306
    E-ISSN: 1098-5549
    Source: HighWire Press (Free Journals)
    Source: Hellenic Academic Libraries Link
    Source: PubMed Central
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  • 5
    Language: English
    In: Nucleic acids research, 2020-02-20, Vol.48 (3), p.1271-1284
    Description: Abstract The healing of broken chromosomes by de novo telomere addition, while a normal developmental process in some organisms, has the potential to cause extensive loss of heterozygosity, genetic disease, or cell death. However, it is unclear how de novo telomere addition (dnTA) is regulated at DNA double-strand breaks (DSBs). Here, using a non-essential minichromosome in fission yeast, we identify roles for the HR factors Rqh1 helicase, in concert with Rad55, in suppressing dnTA at or near a DSB. We find the frequency of dnTA in rqh1Δ rad55Δ cells is reduced following loss of Exo1, Swi5 or Rad51. Strikingly, in the absence of the distal homologous chromosome arm dnTA is further increased, with nearly half of the breaks being healed in rqh1Δ rad55Δ or rqh1Δ exo1Δ cells. These findings provide new insights into the genetic context of highly efficient dnTA within HR intermediates, and how such events are normally suppressed to maintain genome stability.
    Subject(s): Chromosomes, Fungal - genetics ; DNA Breaks, Double-Stranded ; DNA Helicases - genetics ; DNA-Binding Proteins - genetics ; Exodeoxyribonucleases - genetics ; Gene Expression Regulation, Fungal - genetics ; Genome Integrity, Repair and ; Genome, Fungal - genetics ; Genomic Instability - genetics ; Loss of Heterozygosity - genetics ; Rad51 Recombinase - genetics ; Recombinational DNA Repair - genetics ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe Proteins - genetics ; Telomere - genetics
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 6
    Language: English
    In: Nucleic acids research, 2012-10, Vol.40 (19), p.9633-9646
    Description: Faithful chromosome segregation in meiosis is crucial to form viable, healthy offspring and in most species, it requires programmed recombination between homologous chromosomes. In fission yeast, meiotic recombination is initiated by Rec12 (Spo11 homolog) and generates single Holliday junction (HJ) intermediates, which are resolved by the Mus81-Eme1 endonuclease to generate crossovers and thereby allow proper chromosome segregation. Although Mus81 contains the active site for HJ resolution, the regulation of Mus81-Eme1 is unclear. In cells lacking Nse5-Nse6 of the Smc5-Smc6 genome stability complex, we observe persistent meiotic recombination intermediates (DNA joint molecules) resembling HJs that accumulate in mus81Δ cells. Elimination of Rec12 nearly completely rescues the meiotic defects of nse6Δ and mus81Δ single mutants and partially rescues nse6Δ mus81Δ double mutants, indicating that these factors act after DNA double-strand break formation. Likewise, expression of the bacterial HJ resolvase RusA partially rescues the defects of nse6Δ, mus81Δ and nse6Δ mus81Δ mitotic cells, as well as the meiotic defects of nse6Δ and mus81Δ cells. Partial rescue likely reflects the accumulation of structures other than HJs, such as hemicatenanes, and an additional role for Nse5-Nse6 most prominent during mitotic growth. Our results indicate a regulatory role for the Smc5-Smc6 complex in HJ resolution via Mus81-Eme1.
    Subject(s): Cell Cycle Proteins - physiology ; Chromosomal Proteins, Non-Histone - genetics ; Chromosomal Proteins, Non-Histone - physiology ; Chromosomes ; Crossing Over, Genetic ; DNA ; DNA Breaks, Double-Stranded ; DNA damage ; Endonuclease ; Escherichia coli Proteins - metabolism ; Gene Deletion ; Genetic crosses ; Genome Integrity, Repair and ; Genomes ; Holliday Junction Resolvases - metabolism ; Holliday junctions ; homologous recombination ; Joints ; Meiosis ; Meiosis - genetics ; Mitosis - genetics ; Recombination ; Recombinational DNA Repair ; Resolvase ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - physiology
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 7
    Language: English
    In: Molecular and Cellular Biology, 2011-06-01, Vol.31 (11), p.2299-2310
    Description: Article Usage Stats Services MCB Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue MCB About MCB Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy MCB RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0270-7306 Online ISSN: 1098-5549 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to MCB .asm.org, visit: MCB       
    Subject(s): Blotting, Western ; Carrier Proteins - chemistry ; Chromosomal Proteins, Non-Histone - chemistry ; Chromosomal Proteins, Non-Histone - metabolism ; Crystallography, X-Ray ; DNA Repair ; Humans ; Mass Spectrometry ; Models, Molecular ; Mutation ; Protein Structure, Quaternary ; Schizosaccharomyces ; Schizosaccharomyces pombe Proteins - chemistry ; Schizosaccharomyces pombe Proteins - metabolism ; Small Ubiquitin-Related Modifier Proteins - biosynthesis ; Small Ubiquitin-Related Modifier Proteins - metabolism ; Sumoylation ; Ubiquitin-Conjugating Enzymes - chemistry ; Ubiquitin-Conjugating Enzymes - metabolism
    ISSN: 0270-7306
    E-ISSN: 1098-5549
    Source: HighWire Press (Free Journals)
    Source: Hellenic Academic Libraries Link
    Source: PubMed Central
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  • 8
    Language: English
    In: The Journal of biological chemistry, 2011-03-25, Vol.286 (12), p.10238-10247
    Description: SUMOylation of proteins is a cyclic process that requires both conjugation and deconjugation of SUMO moieties. Besides modification by a single SUMO, SUMO chains have also been observed, yet the dynamics of SUMO conjugation/deconjugation remain poorly understood. Using a non-deconjugatable form of SUMO we demonstrate the underappreciated existence of SUMO chains in vivo, we highlight the importance of SUMO deconjugation, and we demonstrate the highly dynamic nature of the SUMO system. We show that SUMO-specific proteases (SENPs) play a crucial role in the dynamics of SUMO chains in vivo by constant deconjugation. Preventing deSUMOylation in Schizosaccharomyces pombe results in slow growth and a sensitivity to replication stress, highlighting the biological requirement for deSUMOylation dynamics. Furthermore, we present the mechanism of SUMO chain deconjugation by SENPs, which occurs via a stochastic mechanism, resulting in cleavage anywhere within a chain. Our results offer mechanistic insights into the workings of deSUMOylating proteases and highlight their importance in the homeostasis of (poly)SUMO-modified substrates.
    Subject(s): Deubiquitination ; Dynamics ; Enzyme Mechanisms ; Enzymology ; HEK293 Cells ; HeLa Cells ; Humans ; Peptide Hydrolases - genetics ; Peptide Hydrolases - metabolism ; Protease ; Proteolytic Enzymes ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - metabolism ; Site-directed Mutagenesis ; SUMO Chains ; SUMO-1 Protein - genetics ; SUMO-1 Protein - metabolism ; Sumoylation ; Sumoylation - physiology ; Ubiquitin
    ISSN: 0021-9258
    E-ISSN: 1083-351X
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    In: Nature structural & molecular biology, 2009-05, Vol.16 (5), p.509-516
    Description: Rad60 family members contain functionally enigmatic, integral SUMO-like domains (SLDs). We show here that despite their divergence from SUMO, each Rad60 SLD interacts with a subset of SUMO pathway enzymes: SLD2 specifically binds the SUMO E2 conjugating enzyme (Ubc9), whereas SLD1 binds the SUMO E1 (Fub2, also called Uba2) activating and E3 (Pli1, also called Siz1 and Siz2) specificity enzymes. The molecular basis of this selectivity is revealed by our 0.97-A resolution crystal structure of Rad60 SLD2, which shows that apart from the conserved non-substrate SUMO:Ubc9 interface, the surface features of SLD2 are distinct from those of SUMO. Abrogation of the SLD2:Ubc9 FEG motif-dependent interaction results in hypersensitivity to genotoxic stress and an increase in spontaneous recombination associated with aberrant replication forks. Our results provide a mechanistic basis for the near-synonymous roles of Rad60 and SUMO in survival of genotoxic stress and suggest unprecedented DNA-damage-response functions for SLDs in regulating sumoylation.
    Subject(s): Binding sites ; Cell Survival ; Chromosomal Proteins, Non-Histone - chemistry ; Chromosomal Proteins, Non-Histone - metabolism ; Crystal structure ; Crystallography, X-Ray ; DNA Damage ; DNA Repair ; Enzymes ; Genome Stability ; Genomic Instability ; Health aspects ; Molecular biology ; Molecular Mimicry ; Mutant Proteins - metabolism ; Physiological aspects ; Post-translational modification ; Protein Binding ; Protein Structure, Tertiary ; Rad60 ; Recombination, Genetic - genetics ; Schizosaccharomyces - cytology ; Schizosaccharomyces - enzymology ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - chemistry ; Schizosaccharomyces pombe Proteins - metabolism ; Small Ubiquitin-Related Modifier Proteins - chemistry ; Small Ubiquitin-Related Modifier Proteins - metabolism ; Structure ; SUMO ; Ubc9 ; Ubiquitin ; Ubiquitin-Conjugating Enzymes - metabolism
    ISSN: 1545-9993
    E-ISSN: 1545-9985
    Source: Academic Search Ultimate
    Source: Nature Journals Online
    Source: Get It Now
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  • 10
    Language: English
    In: The EMBO journal, 2003-03-17, Vol.22 (6), p.1419-1430
    Description: We have examined the genetic requirements for efficient repair of a site‐specific DNA double‐strand break (DSB) in Schizosaccharomyces pombe. Tech nology was developed in which a unique DSB could be generated in a non‐essential minichromosome, Ch16, using the Saccharomyces cerevisiae HO‐endonuclease and its target site, MATa. DSB repair in this context was predominantly through interchromosomal gene conversion. We found that the homologous recombination (HR) genes rhp51+, rad22A+, rad32+ and the nucleotide excision repair gene rad16+ were required for efficient interchromosomal gene conversion. Further, DSB‐induced cell cycle delay and efficient HR required the DNA integrity checkpoint gene rad3+. Rhp55 was required for interchromosomal gene conversion; however, an alternative DSB repair mechanism was used in an rhp55Δ background involving ku70+ and rhp51+. Surprisingly, DSB‐induced minichromosome loss was significantly reduced in ku70Δ and lig4Δ non‐homologous end joining (NHEJ) mutant backgrounds compared with wild type. Furthermore, roles for Ku70 and Lig4 were identified in suppressing DSB‐induced chromosomal rearrangements associated with gene conversion. These findings are consistent with both competitive and cooperative interactions between components of the HR and NHEJ pathways.
    Subject(s): Chromosomes, Fungal ; Deoxyribonucleases, Type II Site-Specific - genetics ; Deoxyribonucleases, Type II Site-Specific - metabolism ; DNA Damage ; DNA integrity checkpoint ; DNA Repair - genetics ; DNA, Fungal - genetics ; DNA, Fungal - metabolism ; Fungal Proteins - genetics ; Fungal Proteins - metabolism ; Gamma Rays ; Gene Conversion ; Genes, Fungal ; HO-endonuclease ; homologous recombination ; Models, Biological ; Mutation ; non-homologous end joining ; Recombination, Genetic ; Saccharomyces cerevisiae - genetics ; Saccharomyces cerevisiae Proteins - genetics ; Saccharomyces cerevisiae Proteins - metabolism ; Schizosaccharomyces - genetics ; Schizosaccharomyces - radiation effects ; site-specific DNA double-strand break
    ISSN: 0261-4189
    ISSN: 1460-2075
    E-ISSN: 1460-2075
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: Get It Now
    Source: Wiley-Blackwell Full Collection 2014
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