Replication Checkpoint Kinase Cds1 Regulates Recombinational Repair Protein Rad60

Boddy, Michael N.; Shanahan, Paul; McDonald, W. Hayes; López-Girona, Antonia; Noguchi, Eishi; Yates, John R.; Russell, Paul

doi:10.1128/mcb.23.16.5939-5946.2003

Cited by 87 publications

(123 citation statements)

References 49 publications

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“…The Rfp1-SUMO interaction was predictable based on the identification of SIM motifs in Rfp1. Uniquely, Rad60 and its homologues share the structural feature of tandem SLDs at their C-termini ( Figure 5A; (Boddy et al, 2003;Novatchkova et al, 2005)). Therefore, we tested for interaction between Rfp1 and the Rad60 SLDs.…”

Section: Identification Of Dna Repair Protein Rad60 As a Potential Slmentioning

confidence: 99%

SUMO-targeted ubiquitin ligases in genome stability

Prudden

Pébernard

Raffa

et al. 2007

EMBO J

307

389

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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.

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Section: Identification Of Dna Repair Protein Rad60 As a Potential Slmentioning

confidence: 99%

SUMO-targeted ubiquitin ligases in genome stability

Prudden

Pébernard

Raffa

et al. 2007

EMBO J

307

389

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“…The Rad60 -Smc5ϩ6 physical interaction and the overlapping set of genetic interactions displayed by rad60 and nse mutants suggests that these proteins have codependent functions (Morishita et al, 2002;. Unlike the Nse proteins, however, Rad60 interacts weakly with components of the Smc5ϩ6 complex (Morishita et al, 2002;Boddy et al, 2003;McDonald et al, 2003). That is, the Nse proteins coprecipitate robustly with the Smc5ϩ6 complex components when expressed at their endogenous levels ( Figure 1, B and C; McDonald et al, 2003).…”

mentioning

confidence: 99%

“…Proteins in the eluate were precipitated and subjected to mass spectrometry analysis. We have used this system extensively for identification of protein complexes in S. pombe and have thus generated a comprehensive list of common background proteins (Boddy et al, 2001;Boddy et al, 2003;McDonald et al, 2003). Comparison of the Smc5-TAP data set with previous purifications allowed us to exclude common background such as ribosomal proteins, abundant metabolic enzymes, and actin.…”

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confidence: 99%

Nse1, Nse2, and a Novel Subunit of the Smc5-Smc6 Complex, Nse3, Play a Crucial Role in Meiosis

Pébernard

McDonald

Pavlova

et al. 2004

MBoC

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113

150

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The structural maintenance of chromosomes (SMC) family of proteins play key roles in the organization, packaging, and repair of chromosomes. Cohesin (Smc1؉3) holds replicated sister chromatids together until mitosis, condensin (Smc2؉4) acts in chromosome condensation, and Smc5؉6 performs currently enigmatic roles in DNA repair and chromatin structure. The SMC heterodimers must associate with non-SMC subunits to perform their functions. Using both biochemical and genetic methods, we have isolated a novel subunit of the Smc5؉6 complex, Nse3. Nse3 is an essential nuclear protein that is required for normal mitotic chromosome segregation and cellular resistance to a number of genotoxic agents. Epistasis with Rhp51 (Rad51) suggests that like Smc5؉6, Nse3 functions in the homologous recombination based repair of DNA damage. We previously identified two non-SMC subunits of Smc5؉6 called Nse1 and Nse2. Analysis of nse1-1, nse2-1, and nse3-1 mutants demonstrates that they are crucial for meiosis. The Nse1 mutant displays meiotic DNA segregation and homologous recombination defects. Spore viability is reduced by nse2-1 and nse3-1, without affecting interhomolog recombination. Finally, genetic interactions shared by the nse mutants suggest that the Smc5؉6 complex is important for replication fork stability. INTRODUCTIONBoth endogenous and exogenous agents constantly threaten genomic integrity. The DNA double-strand break (DSB) is a potentially life-threatening lesion for a cell and can occur spontaneously during growth, as part of a programmed event such as meiosis or as the result of exposure to environmental genotoxic agents. Multiple mechanisms exist to repair DSBs, including nonhomologous end joining and homologous recombination (HR) (Paques and Haber, 1999;Symington, 2002). The HR pathway serves to maintain all original genetic information during DSB repair. Many components of that pathway have been identified and characterized (Paques and Haber, 1999;Symington, 2002). HR involves multiple steps. The DSB is first resected to generate a recombinogenic 3Ј overhang that invades a homologous sequence (e.g., sister chromatid), forming a displacement or D-loop. The invasion step is catalyzed by a number of proteins including the Escherichia coli RecA homologue, Rad51. D-loop formation primes repair synthesis, which is followed by resolution of the recombined duplexes and ligation, producing intact duplex DNA molecules (Paques and Haber, 1999;Symington, 2002). The resolution of recombined DNA duplexes can yield products in which there has been reciprocal exchange of flanking markers (crossover) or not. During mitotic growth gene conversion is infrequently accompanied by crossover, whereas during meiosis, crossover recombination is much more prevalent (Paques and Haber, 1999).Efficient DNA repair requires modulation of both local and higher order chromatin structure. Interestingly, the structural maintenance of chromosomes (SMC) proteins have recently been recognized as important players in DNA repair (Hirano, 2002;Jessberger...

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“…p53 promotes DNA repair or apoptosis by directly regulating the expression of genes such as p48, DR5, BAX, PUMA and NOXA [2,8]. CHK2 (cds1) in fission yeast was shown to interact with RAD60, a protein required for recombinational repair, at stalled replication forks [9]. In mammalian cells, it was shown that CHK2 promotes homologous recombination (HR) and non-homologous end-joining (NHEJ) of DNA double-strand breaks through phosphorylation of BRCA1 on serine 988 [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Irofulven induces replication-dependent CHK2 activation related to p53 status

Wang

Wiltshire

Senft

et al. 2007

Biochemical Pharmacology

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CHK2 and p53 are frequently mutated in human cancers. CHK2 is known to phosphorylate and stabilize p53. CHK2 has also been implicated in DNA repair and apoptosis induction. However, whether p53 affects CHK2 activation and whether CHK2 activation modulates chemosensitivity are unclear. In this study, we found that in response to the DNA damage agent, irofulven, CHK2 activation, rather than its expression, is inversely correlated to p53 status. Irofulven inhibits DNA replication and induces chromosome aberrations (breaks and radials) and p53-dependent cell cycle arrest. Pretreatment of cells with the DNA polymerase inhibitor, aphidicolin, resulted in reduction of irofulven-induced CHK2 activation and foci formation, indicating that CHK2 activation by irofulven is replication-dependent. Furthermore, by using ovarian cancer cell lines expressing dominant-negative CHK2 and CHK2-knockout HCT116 cells, we found that CHK2 activation contributes to the control of S and G2/M cell cycle arrests, but not chemosensitivity to irofulven. Overall, this study demonstrates that in response to irofulven-induced DNA damage, the activation of CHK2 is dependent on DNA replication and related to p53 status. By controlling cell cycle arrest and DNA replication, p53 affects CHK2 activation. CHK2 activation contributes to cell cycle arrest, but not chemosensitivity.

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Replication Checkpoint Kinase Cds1 Regulates Recombinational Repair Protein Rad60

Cited by 87 publications

References 49 publications

SUMO-targeted ubiquitin ligases in genome stability

SUMO-targeted ubiquitin ligases in genome stability

Nse1, Nse2, and a Novel Subunit of the Smc5-Smc6 Complex, Nse3, Play a Crucial Role in Meiosis

Irofulven induces replication-dependent CHK2 activation related to p53 status

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