Structure-based predictions of Rad1, Rad9, Hus1 and Rad17 participation in sliding clamp and clamp-loading complexes

Venclovas, C̆eslovas; Thelen, Michael P.

doi:10.1093/nar/28.13.2481

Cited by 236 publications

(224 citation statements)

References 55 publications

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“…Rad9 has two predicted domains (Rauen et al 2000;Venclovas and Thelen 2000;Roos-Mattjus et al 2003). The N-terminal two-thirds of the protein (∼270 amino acids) forms a PCNA-like structure that associates with Hus1 and Rad1 to yield the 9-1-1 clamp complex (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Rad9–Hus1–Rad1 (9–1–1) clamp activates checkpoint signaling via TopBP1

Delacroix¹,

Wagner²,

Kobayashi³

et al. 2007

Genes Dev.

417

415

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DNA replication stress triggers the activation of Checkpoint Kinase 1 (Chk1) in a pathway that requires the independent chromatin loading of the ATRIP-ATR (ATR-interacting protein/ATM [ataxia-telangiectasia mutated]-Rad3-related kinase) complex and the Rad9-Hus1-Rad1 (9-1-1) clamp. We show that Rad9's role in Chk1 activation is to bind TopBP1, which stimulates ATR-mediated Chk1 phosphorylation via TopBP1's activation domain (AD), a domain that binds and activates ATR. Notably, fusion of the AD to proliferating cell nuclear antigen (PCNA) or histone H2B bypasses the requirement for the 9-1-1 clamp, indicating that the 9-1-1 clamp's primary role in activating Chk1 is to localize the AD to a stalled replication fork.Supplemental material is available at http://www.genesdev.org.

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Section: Resultsmentioning

confidence: 99%

The Rad9–Hus1–Rad1 (9–1–1) clamp activates checkpoint signaling via TopBP1

Delacroix¹,

Wagner²,

Kobayashi³

et al. 2007

Genes Dev.

417

415

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“…Upstream of Rad53, Rad9 and two more protein complexes signal the presence of DNA damage and fully activate Rad53 (De la Torre-Ruiz et al, 1998;Sanchez et al, 1999;Rouse and Jackson, 2002). One complex is a replication factor C (RFC)-like complex, where Rad24 interacts with four small RFC-subunits (Griffiths et al, 1995); the other complex, formed by Rad17, Ddc1 and Mec3 proteins, shows similarity to the sliding clamp PCNA (Venclovas and Thelen, 2000). In case of DNA damage the PCNA-like structure is loaded onto DNA by the RFC-like complex (Longhese et al, 1998, Melo et al, 2001.…”

Section: Genetic Interactions Between Mph1 and Srs2 Mutationsmentioning

confidence: 99%

Genetic evidence for a role of Saccharomyces cerevisiae Mph1 in recombinational DNA repair under replicative stress

Panico

Ede

Schildmann

et al. 2009

Yeast

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In yeast as in human, DNA helicases play critical roles in assisting replication fork progression. The Saccharomyces cerevisiae MPH1 gene, homologue of human FANCM, has been involved in homologous recombination and DNA repair. We describe a synthetic growth defect of an mph1 deletion if combined with an srs2 deletion that can result -depending on the genetic background -in synthetic lethality. The lethality is suppressed by mutations in homologous recombination (rad51, rad52, rad55, rad57 ) and in the DNA damage checkpoint (rad9, rad24, rad17 ). Importantly, rad54 and mph1, epistatic for damage sensitivity, are subadditive for spontaneous mutator phenotype. Therefore, Mph1 could be placed at the Rad51-mediated strand invasion process, with a function distinct from Rad54. Moreover, siz1 mutation is viable with mph1 and additive for DNA damage sensitivity. mph1 srs2 double mutants, isolated in a background where they are viable, are synergistically sensitive to DNA damage. Moderate overexpression of SGS1 partially suppresses this sensitivity. Finally, we observe an epistatic relationship in terms of sensitivity to camptothecin of mms4 or mus81 to mph1. Overall, our results support a role of Mph1 in assisting replication progression. We propose two models for the resumption of DNA synthesis under replicative stress where Mph1 is placed at the sister chromatid interaction step.

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“…DISCUSSION Rad9, Hus1, Rad1, and Rad17 are key participants in the complex checkpoint signaling pathways activated by genotoxins. Although an elegant biochemical model has been presented describing the functions of these proteins, it remains unclear how these protein complexes are regulated (13). In the present studies we examined the roles of other checkpoint signaling proteins and the DNA replication apparatus in the binding of the 9-1-1 complex to DNA in response to a panel of genotoxic agents.…”

Section: -1-1 Chromatin Association Is An Early Eventmentioning

confidence: 99%

Genotoxin-induced Rad9-Hus1-Rad1 (9-1-1) Chromatin Association Is an Early Checkpoint Signaling Event

Roos-Mattjus¹,

Vroman²,

Burtelow³

et al. 2002

Journal of Biological Chemistry

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Rad17, Rad1, Hus1, and Rad9 are key participants in checkpoint signaling pathways that block cell cycle progression in response to genotoxins. Biochemical and molecular modeling data predict that Rad9, Hus1, and Rad1 form a heterotrimeric complex, dubbed 9-1-1, which is loaded onto chromatin by a complex of Rad17 and the four small replication factor C (RFC) subunits (Rad17-RFC) in response to DNA damage. It is unclear what checkpoint proteins or checkpoint signaling events regulate the association of the 9-1-1 complex with DNA. Here we show that genotoxin-induced chromatin binding of 9-1-1 does not require the Rad9-inducible phosphorylation site (Ser-272). Although we found that Rad9 undergoes an additional phosphatidylinositol 3-kinase-related kinase (PIKK)-dependent posttranslational modification, we also show that genotoxin-triggered 9-1-1 chromatin binding does not depend on the catalytic activity of the PIKKs ataxia telangiectasia-mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), or DNA-PK. Additionally, 9-1-1 chromatin binding does not require DNA replication, suggesting that the complex can be loaded onto DNA in response to DNA structures other than stalled DNA replication forks. Collectively, these studies demonstrate that 9-1-1 chromatin binding is a proximal event in the checkpoint signaling cascade.DNA damage and replication stress activate checkpoint signaling pathways that block cell cycle progression, activate programmed cell death, and influence DNA repair. Biochemical and genetic studies in yeasts and mammals have identified many of the key components and arranged them into checkpoint signaling cascades (reviewed Refs. 1 and 2). The phosphatidylinositol-3-kinase-related kinases (PIKK) 1 ATM and ATR are central components of the evolutionarily conserved checkpoint signaling pathways (3). In response to genotoxins, ATM and ATR phosphorylate and activate the protein kinases Chk1 and Chk2 (4). Activated ATM, ATR, Chk1, and Chk2 then phosphorylate additional checkpoint proteins, including Rad9, BRCA1, p53, Cdc25A, Cdc25C, Nbs1, and other proteins that mediate checkpoint activation and DNA repair.In addition to the PIKKs, the checkpoint proteins, Rad9, Hus1, Rad1, and Rad17 (using Schizosaccharomyces pombe nomenclature) are key elements of checkpoint signaling pathways that are conserved from the yeasts to humans. Disruption of these genes in S. pombe blocks genotoxin-induced Chk1 activation (5). Correspondingly, Hus1 and Rad17 are also required for genotoxin-induced Chk1 activation in mammals (6, 7). Such studies suggest that these proteins function early in the checkpoint signaling pathway. Recent biochemical studies further support this notion. Rad9, Hus1, and Rad1 form a stable heterotrimeric complex (the 9-1-1 complex) (8, 9) that, based on biochemical, biophysical, and molecular modeling studies, is predicted to resemble PCNA (8, 10 -14). PCNA subunits assemble into a toroidal clamp complex that is loaded around DNA by the clamp loader, replication factor C (p140-RFC), a protein compl...

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Structure-based predictions of Rad1, Rad9, Hus1 and Rad17 participation in sliding clamp and clamp-loading complexes

Cited by 236 publications

References 55 publications

The Rad9–Hus1–Rad1 (9–1–1) clamp activates checkpoint signaling via TopBP1

The Rad9–Hus1–Rad1 (9–1–1) clamp activates checkpoint signaling via TopBP1

Genetic evidence for a role of Saccharomyces cerevisiae Mph1 in recombinational DNA repair under replicative stress

Genotoxin-induced Rad9-Hus1-Rad1 (9-1-1) Chromatin Association Is an Early Checkpoint Signaling Event

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