Yeast Checkpoint Genes in DNA Damage Processing: Implications for Repair and Arrest

Lydall, David; Weinert, Ted

doi:10.1126/science.270.5241.1488

Cited by 377 publications

(403 citation statements)

References 26 publications

(4 reference statements)

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“…It is still not known whether there exist discrete but overlapping regulatory pathways triggered separately by unreplicated DNA and by DNA damage or whether genes such as the RAD9 group are simply additionally required to activate the DNA damage checkpoint in an otherwise identical signal transduction pathway. It has been shown that RAD9, MEC3, RAD24, and RAD17 play a role in processing DNA lesions and therefore could be involved in generating the signal to activate the checkpoint at G~/S and G2/M (Lydall and Weinert 1995). However, it was not shown whether the effect on DNA processing was directly attributable to these proteins or attributable to defects in signaling that occur in these mutants.…”

mentioning

confidence: 79%

“…Recently, RAD9, RAD17, RAD24, and MEC3 have been postulated to be involved in processing cdcl3-induced lesions near the telomeres (Garvik et al 1995;Lydall and Weinert 1995). Although RAD9 was shown to act differently from RAD24, MEC3, and RAD17 in processing DNA damage, all four genes appear to act in the same pathway with respect to cell-cycle arrest and would be expected to have phenotypes similar to rad9 mutants in the RNR3 transcription assay.…”

Section: Transcriptional Response Of Other Checkpoint Mutants Shows Rmentioning

confidence: 99%

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RAD9 and DNA polymerase epsilon form parallel sensory branches for transducing the DNA damage checkpoint signal in Saccharomyces cerevisiae.

Navas¹,

Sánchez²,

Elledge³

1996

Genes Dev.

156

130

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In response to DNA damage and replication blocks, yeast cells arrest at distinct points in the cell cycle and induce the transcription of genes whose products facilitate DNA repair. Examination of the inducibility of RNR3 in response to UV damage has revealed that the various checkpoint genes can be arranged in a pathway consistent with their requirement to arrest cells at different stages of the cell cycle. While RADg, RAD24, and MEC3 are required to activate the DNA damage checkpoint when cells are in G1 or G2, POL2 is required to sense UV damage and replication blocks when cells are in S phase. The phosphorylation of the essential central transducer, Rad53p, is dependent on POL2 and RAD9 in response to UV damage, indicating that RAD53 functions downstream of both these genes. Mutants defective for both pathways are severely deficient in Rad53p phosphorylation and RNR3 induction and are significantly more sensitive to DNA damage and replication blocks than single mutants alone. These results show that POL2 and RAD9 function in parallel branches for sensing and transducing the UV DNA damage signal. Each of these pathways subsequently activates the central transducers Meclp/Esrlp/Sad3p and Rad53p/Mec2p/Sadlp, which are required for both cell-cycle arrest and transcriptional responses.

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mentioning

confidence: 79%

Section: Transcriptional Response Of Other Checkpoint Mutants Shows Rmentioning

confidence: 99%

RAD9 and DNA polymerase epsilon form parallel sensory branches for transducing the DNA damage checkpoint signal in Saccharomyces cerevisiae.

Navas¹,

Sánchez²,

Elledge³

1996

Genes Dev.

156

130

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“…Rad1 sp is similar to the Ustilago Rec1 exonuclease, the putative human Rad1 sp homolog (hRad1) displays exonuclease activity [15,16•], and Rad17 sp has limited similarity to replication factor C (RFC) [17]. Furthermore, S. cerevisiae homologs of Rad1 and Rad17 have been implicated in the processing of DNA damage [18]. The most interesting similarity is that of Rad3 sp to DNA-dependent protein kinase (DNA-PK) [19,20].…”

Section: The Schizosaccharomyces Pombe G 2 Dna Damage Checkpointmentioning

confidence: 99%

“…Several proteins of the Rad24 sc group are structurally similar to proteins involved in DNA metabolism (Table 1), and are required for the processing of damaged DNA [18]. Both Rad9 sc and Ddc1 sc , however, are phosphorylated after DNA damage in a Mec1 sc dependent manner, indicating that they lie downstream of Mec1 sc [45••,51•,57••].…”

Section: The Schizosaccharomyces Pombe G 2 Dna Damage Checkpointmentioning

confidence: 99%

Mitotic DNA damage and replication checkpoints in yeast

Rhind

Russell

1998

Current Opinion in Cell Biology

175

129

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“…The DNA damage checkpoint signal is generated in response to ssDNA detection by the ATR-ATRIP and 9-1-1 complexes (Lydall and Weinert 1995;Melo et al 2001;Zou and Elledge 2003). The DNA damage checkpoint has been shown to be required for efficient DSB repair where Rad24 Sc is required for resection and, thus, ssDNA production (Aylon and Kupiec 2003), while Rad9 Sc has been shown to limit ssDNA production associated with DSB repair (Lazzaro et al 2008).…”

Section: Checkpoint-dependent Ssdna Regulation and Dsb Repairmentioning

confidence: 99%

Break-induced ATR and Ddb1–Cul4^Cdt2 ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast

Moss

Tinline-Purvis²,

Walker³

et al. 2010

Genes Dev.

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Nucleotide synthesis is a universal response to DNA damage, but how this response facilitates DNA repair and cell survival is unclear. Here we establish a role for DNA damage-induced nucleotide synthesis in homologous recombination (HR) repair in fission yeast. Using a genetic screen, we found the Ddb1-Cul4 Cdt2 ubiquitin ligase complex and ribonucleotide reductase (RNR) to be required for HR repair of a DNA double-strand break (DSB). The Ddb1-Cul4 Cdt2 ubiquitin ligase complex is required for degradation of Spd1, an inhibitor of RNR in fission yeast. Accordingly, deleting spd1 + suppressed the DNA damage sensitivity and the reduced HR efficiency associated with loss of ddb1 + or cdt2 + . Furthermore, we demonstrate a role for nucleotide synthesis in postsynaptic gap filling of resected ssDNA ends during HR repair. Finally, we define a role for Rad3 (ATR) in nucleotide synthesis and HR through increasing Cdt2 nuclear levels in response to DNA damage. Our findings support a model in which breakinduced Rad3 and Ddb1-Cul4 Cdt2 ubiquitin ligase-dependent Spd1 degradation and RNR activation promotes postsynaptic ssDNA gap filling during HR repair.[Keywords: Rad3; Ddb1-Cul4 Cdt2 ubiquitin ligase; Spd1; ribonucleotide reductase; homologous recombination repair; fission yeast] Supplemental material is available at http://www.genesdev.org. Received July 16, 2010; revised version accepted October 15, 2010. DNA double-strand breaks (DSBs) are potentially lethal lesions that, if left undetected or repaired incorrectly, can threaten the integrity of the genome. DSBs arise at a low frequency during normal cell metabolism and can also arise from exposure to DNA-damaging agents such as ionizing radiation (IR) (Shrivastav et al. 2008), potentially leading to chromosomal rearrangements, cancer, or cell death (Pfeiffer et al. 2000). Consequently, an intricate network of cellular responses for detection and accurate repair of such lesions exists within the cell (Jackson and Bartek 2009).Cells have evolved two distinct repair pathways to maintain genome integrity following a DSB: nonhomologous end-joining (NHEJ), in which DNA ends are directly ligated, and homologous recombination (HR) (Shrivastav et al. 2008). In yeast, HR involves the RAD52 epistasis group (Krogh and Symington 2004) and uses a homologous sequence as a template for repair-typically the sister chromatid or, less frequently, the homologous chromosome (Kadyk and Hartwell 1992). Repair is initiated by 59-39 resection of the broken ends to form a 39 ssDNA overhang. This is a two-step process in which MRX/MRN (Mre11-Rad50-Xrs2 in Saccharomyces cerevisiae (Sung 1997;Sugawara et al. 2003;Wolner et al. 2003;Haruta et al. 2008). Stabilization of the nucleoprotein filament is achieved through interaction between Rad51 and Rad54; strand invasion is then initiated, resulting in the formation of a displacement (D) loop (Petukhova et al. 1998;Mazin et al. 2003;Sugawara et al. 2003). RPA further functions postsynaptically to stabilize DNA pairing and possibly the displaced ssD...

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Yeast Checkpoint Genes in DNA Damage Processing: Implications for Repair and Arrest

Cited by 377 publications

References 26 publications

RAD9 and DNA polymerase epsilon form parallel sensory branches for transducing the DNA damage checkpoint signal in Saccharomyces cerevisiae.

RAD9 and DNA polymerase epsilon form parallel sensory branches for transducing the DNA damage checkpoint signal in Saccharomyces cerevisiae.

Mitotic DNA damage and replication checkpoints in yeast

Break-induced ATR and Ddb1–Cul4^Cdt2 ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast

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Yeast Checkpoint Genes in DNA Damage Processing: Implications for Repair and Arrest

Cited by 377 publications

References 26 publications

RAD9 and DNA polymerase epsilon form parallel sensory branches for transducing the DNA damage checkpoint signal in Saccharomyces cerevisiae.

RAD9 and DNA polymerase epsilon form parallel sensory branches for transducing the DNA damage checkpoint signal in Saccharomyces cerevisiae.

Mitotic DNA damage and replication checkpoints in yeast

Break-induced ATR and Ddb1–Cul4Cdt2 ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast

Contact Info

Product

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About

Break-induced ATR and Ddb1–Cul4^Cdt2 ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast