A Role for Checkpoint Kinase-Dependent Rad26 Phosphorylation in Transcription-Coupled DNA Repair in Saccharomyces cerevisiae
Open accessAbstract
Upon DNA damage, eukaryotic cells activate a conserved signal transduction cascade known as the DNA damage checkpoint (DDC). We investigated the influence of DDC kinases on nucleotide excision repair (NER) in Saccharomyces cerevisiae and found that repair of both strands of an active gene is affected by Mec1 but not by the downstream checkpoint kinases, Rad53 and Chk1. Repair of the nontranscribed strand (by global genome repair) requires new protein synthesis, possibly reflecting the involvement of Mec1 in the activation of repair genes. In contrast, repair of the transcribed strand by transcription-coupled NER (TC-NER) occurs in the absence of new protein synthesis, and DNA damage results in Mec1-dependent but Rad53-, Chk1-, Tel1-, and Dun1-independent phosphorylation of the TC-NER factor Rad26, a member of the Swi/Snf group of ATP-dependent translocases and yeast homologue of Cockayne syndrome B. Mutation of the Rad26 phosphorylation site results in a decrease in the rate of TC-NER, pointing to direct activation of Rad26 by Mec1 kinase. These findings establish a direct role for Mec1 kinase in transcription-coupled repair, at least partly via phosphorylation of Rad26, the main transcription-repair coupling factor.
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Written from the paper’s full text.
TL;DR
In *Saccharomyces cerevisiae*, Mec1-dependent phosphorylation of the transcription-coupled NER factor Rad26 is required for optimal transcription-coupled repair, while global genome repair also requires Mec1 but likely through new protein synthesis. Rad26 is phosphorylated primarily on serine 27 after DNA damage, and a phospho-deficient Rad26 mutant slows TC-NER without causing UV sensitivity.
Key findings
- NER of both strands of the active *RPB2* gene is impaired in *mec1Δ sml1Δ* cells, but not in *chk1Δ* or *rad53Δ sml1Δ* cells; cycloheximide blocks nontranscribed-strand repair but not transcribed-strand repair.
- DNA damage induces Rad26 phosphorylation that requires Mec1 kinase activity but not Rad53, Chk1, Tel1, or Dun1; phosphorylation is reversed by phosphatase and occurs after UV and chemical DNA-damaging treatments, but not heat shock, osmotic shock, or 6-azauracil.
- Rad26 is phosphorylated primarily on S27; mass spectrometry also identified S27 and S30 phosphorylation, and mutation of S27 abolished the damage-induced mobility shift.
- The Rad26 S27A mutant delays TC-NER, extending damage half-life from ∼1.7 h with wild-type RAD26 to ∼2.6 h, while *rad26Δ* cells had >3.5 h; the phosphomimetic S27E mutant was largely unaffected, but S27E did not rescue the TC-NER defect of *mec1Δ sml1Δ* cells.
Methods
- Congenic W303 *S. cerevisiae* strains, including checkpoint and NER mutants, were grown to early log phase and treated with UV-C, 4NQO, MMS, bleomycin, or H2O2 as indicated.
- Strand-specific NER was measured at nucleotide resolution in a 740-bp *RPB2* fragment after 100 J/m² UV-C, using biotinylated transcribed-strand or nontranscribed-strand probes, HaeIII digestion, *Micrococcus luteus* extract incision at CPDs, and denaturing gel analysis; damage half-lives were quantified by phosphorimager.
- Rad26 phosphorylation was analyzed by SDS-PAGE/Western blotting of Myc-tagged Rad26, immunoprecipitation with phosphatase treatment, site-directed mutagenesis of SQ/TQ motifs, galactose-inducible Mec1 expression, and LC-MS/MS with CID/ETD after Rad26 purification.
Limitations
- Stated: the mechanism by which Rad26 phosphorylation enhances TC-NER remains unknown; no reconstituted yeast TC-NER assay exists to compare modified and unmodified Rad26, and few proteins stably associate with Rad26 for interaction studies.
- Stated: the authors could not rule out residual Rad26 modification escaping detection by SDS-PAGE mobility shift, and they could not rule out that cycloheximide partly impairs checkpoint activation in addition to blocking new protein synthesis.
- Evident from the text: several key genetic and biochemical results are reported as “data not shown,” including UV-sensitivity assays for phosphorylation mutants, ATPase activity of phosphorylated Rad26, Rpb1 ubiquitylation/degradation, and CSB phosphorylation analyses; the paper also notes that slower TC-NER did not translate into increased UV sensitivity, leaving the phenotypic relevance unresolved.
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- Findingreasoning§ Abstract
Repair of the nontranscribed strand by global genome repair requires new protein synthesis.
“Repair of the nontranscribed strand (by global genome repair) requires new protein synthesis, possibly reflecting the involvement of Mec1 in the activation of repair genes.”
Quote in the paperNot a substantial claim- Rests on an assumption: Cycloheximide treatment abolishes synthesis of new proteins.
- Findingown data§ Abstract
Repair of the transcribed strand by transcription-coupled NER occurs in the absence of new protein synthesis.
“In contrast, repair of the transcribed strand by transcription-coupled NER (TC-NER) occurs in the absence of new protein synthesis”
- Also stated in: § RESULTS · plain
“Repair of the TS was not detectably affected by CHX treatment”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · plain
- Findingown data§ Abstract
Rad26 phosphorylation after DNA damage is independent of Rad53, Chk1, Tel1, and Dun1.
“but Rad53-, Chk1-, Tel1-, and Dun1-independent phosphorylation of the TC-NER factor Rad26”
- Also stated in: § RESULTS · hedged
“Damage-induced phosphorylation was abrogated only in cells lacking the Mec1 kinase, supporting the idea that Mec1 directly phosphorylates Rad26 without the involvement of downstream kinases (Fig. 3C).”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · hedged
- Findingown data§ Abstract
Repair of both strands of an active gene is impaired in cells lacking Mec1.
“repair of both strands of an active gene is affected by Mec1”
- Also stated in: § RESULTS · plain
“Interestingly, cells lacking the checkpoint kinase Mec1 exhibited a dramatic impairment of NER, characterized by markedly slower repair of the TS and virtually no repair of the NTS at 4 h post-UV irradiation.”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · plain
- Findingown data§ Abstract
Mutation of the Rad26 phosphorylation site results in a decrease in the rate of TC-NER.
“Mutation of the Rad26 phosphorylation site results in a decrease in the rate of TC-NER”
Quote in the paperSubstantial claim
- Findingown data§ Abstract
DNA damage results in Mec1-dependent phosphorylation of the TC-NER factor Rad26.
“DNA damage results in Mec1-dependent but Rad53-, Chk1-, Tel1-, and Dun1-independent phosphorylation of the TC-NER factor Rad26”
- Also stated in: § RESULTS · plain
“To determine whether a functional DNA damage checkpoint is required for Rad26 phosphorylation, we tested whether the modification occurs in the mec1Δ sml1Δ strain. Interestingly, it did not (Fig. 3A).”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · plain
- Findingown data§ Abstract
NER is not compromised in cells lacking the downstream checkpoint kinases Rad53 and Chk1.
“but not by the downstream checkpoint kinases, Rad53 and Chk1”
- Also stated in: § RESULTS · plain
“Interestingly, however, no NER defects were observed in the chk1Δ and rad53Δ sml1Δ strains (Fig. 1B and data not shown).”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · plain
- Findingown data§ RESULTS
CHX addition does not affect Rad26 phosphorylation after DNA damage.
“CHX addition did not affect Rad26 phosphorylation (Fig. 2E).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
Damage half-life was extended from ∼1.7 h in the presence of wild-type RAD26 to ∼2.6 h in the rad26SA mutant.
“so that damage half-life was extended from ∼1.7 h in the presence of wild-type RAD26 to ∼2.6 h in the rad26SA mutant, while damage half-life in rad26Δ cells was >3.5 h (Fig. 5B).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Mutation of the CSB site identified by mass spectrometric analysis does not result in UV sensitivity in human cell lines.
“We found that mutation of the CSB site identified by mass spectrometric analysis does not result in UV sensitivity in human cell lines (data not shown)”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
Rad26 phosphorylation does not occur in the mec1Δ sml1Δ strain.
“To determine whether a functional DNA damage checkpoint is required for Rad26 phosphorylation, we tested whether the modification occurs in the mec1Δ sml1Δ strain. Interestingly, it did not (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Severely delayed TC-NER was observed in cells lacking RAD26 compared to the wild-type control.
“Figure 5A and B shows that, as expected, severely delayed TC-NER was observed in cells lacking RAD26 compared to the wild-type control.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
The DNA-stimulated ATPase activity of phosphorylated Rad26 is not significantly different from that of the unmodified protein in vitro.
“our initial studies suggest that the DNA-stimulated ATPase activity of phosphorylated Rad26 is not significantly different from that of the unmodified protein in vitro (data not shown).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
TC-NER in the rad26SE mutant was largely unaffected.
“TC-NER in the rad26SE mutant (where glutamate mimics persistent phosphorylation) was largely unaffected (Fig. 5A and B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Mutation of Rad26 S27 to glutamic acid did not lead to faster TC-NER in the checkpoint-deficient strain.
“Mutation of Rad26 S27 to a glutamic acid residue did not lead to faster TC-NER in the checkpoint-deficient strain”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
The slower-migrating form of Rad26 represents a phosphorylated form of Rad26.
“The slower-migrating protein was lost after incubation with phosphatase, indicating that it represents a phosphorylated form of Rad26 (Fig. 2B).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Introduction of rad26SE into the mec1Δ sml1Δ strain did not alleviate the TC-NER defect in these cells.
“introduction of this mutant into the mec1Δ sml1Δ strain did not alleviate the TC-NER defect in these cells.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Rad26 is a target for phosphorylation upon DNA damage.
“we identified Rad26 as a target for phosphorylation upon DNA damage.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Treatment with 6-azauracil does not cause a detectable increase in the phosphorylated form of Rad26.
“However, treatment with 6AU did not cause a detectable increase in the phosphorylated form of Rad26 (Fig. 2D)”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Cells expressing the Rad26 alanine mutant exhibited a clear and highly reproducible delay in TC-NER.
“cells expressing the Rad26 alanine mutant exhibited a clear and highly reproducible delay in TC-NER (Fig. 5A, rad26SA)”
- Also stated in: § DISCUSSION · boosted
“Most importantly, mutation of this phosphorylation site to an alanine (preventing phosphorylation), but not to a negatively charged glutamic acid residue (mimicking persistent phosphorylation), leads to a clear delay in TC-NER.”
- Also stated in: § DISCUSSION · hedged
“although rad26SA—but not rad26SE—significantly increased the half-life of UV-induced DNA damage in the transcribed strand, we failed to uncover phenotypic consequences of it.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · boosted
- Findingown data§ RESULTS
Repair of the NTS was not affected by any of the mutations.
“Repair of the NTS was not affected by any of the mutations.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Various chemical DNA-damaging treatments cause Rad26 to be phosphorylated.
“All of these DNA damage-inducing treatments caused Rad26 to be phosphorylated (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Damage half-life in rad26Δ cells was >3.5 h.
“so that damage half-life was extended from ∼1.7 h in the presence of wild-type RAD26 to ∼2.6 h in the rad26SA mutant, while damage half-life in rad26Δ cells was >3.5 h (Fig. 5B).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
TC-NER is virtually undetectable at the RPB2 gene after deletion of RAD26 in the mec1Δ sml1Δ strain.
“even though TC-NER is virtually undetectable at the RPB2 gene after deletion of RAD26 in the mec1Δ sml1Δ strain, no significant increase in UV sensitivity was observed in the mec1Δ sml1Δ rad26Δ strain”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Reintroduction of either RAD26WT or rad26SA brought the rate of TC-NER back to the level of the mec1Δ sml1Δ strain.
“Reintroduction of either RAD26WT or rad26SA brought the rate of TC-NER back to the level of the mec1Δ sml1Δ strain”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Both S27 and S30 of Rad26 are phosphorylated after DNA damage.
“Indeed, MS analysis indicated that both S27 and S30 were phosphorylated in this sample.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
We failed to detect significant changes in Rpb1 ubiquitylation and degradation in cells expressing Rad26 phosphorylation mutants.
“we failed to detect significant changes in Rpb1 ubiquitylation and degradation in cells expressing Rad26 phosphorylation mutants (data not shown).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
The remaining TC-NER in the mec1Δ sml1Δ cells is highly dependent on the presence of Rad26.
“Analysis of TC-NER kinetics in these strains showed that the remaining TC-NER in the mec1Δ sml1Δ cells is highly dependent on the presence of Rad26 (Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
We failed to uncover a phenotypic effect of rad26 or Rad26 phosphorylation on MMS, bleomycin, or hydrogen peroxide sensitivity.
“We also failed to uncover a phenotypic effect of rad26 or Rad26 phosphorylation on MMS, bleomycin, or hydrogen peroxide sensitivity (data not shown).”
Quote in the paperSubstantial claim - Findingreasoning§ DISCUSSION
Only Mec1 affects the rate of TC-NER.
“but only Mec1 affects the rate of TC-NER”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Rad26 is primarily modified on serine 27 (S27).
“Rad26 is primarily modified on serine 27 (S27), part of an SQ motif, which is also the general consensus recognition motif for Mec1 and Tel1 kinases.”
Quote in the paperSubstantial claim- Rests on an assumption: S27 is part of an SQ motif, the general consensus recognition motif for Mec1 and Tel1 kinases.
- Interpretationown data§ RESULTS
The defect in GG-NER observed in the checkpoint-deficient strain is due to defects in induced expression of factors required for dealing with DNA damage.
“Together, these results are consistent with the idea that the defect in GG-NER observed in the checkpoint-deficient strain is due to defects in induced expression of factors required for dealing with DNA damage, while the defect in TC-NER must be caused by a preexisting factor(s).”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
Mec1 kinase has a direct role in transcription-coupled repair, at least partly via phosphorylation of Rad26, the main transcription-repair coupling factor.
“These findings establish a direct role for Mec1 kinase in transcription-coupled repair, at least partly via phosphorylation of Rad26, the main transcription-repair coupling factor.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Abstract
Mec1 kinase directly activates Rad26.
“pointing to direct activation of Rad26 by Mec1 kinase.”
Quote in the paperSubstantial claim - Premisecitation§ Abstract
Cells lacking one of the GG-NER genes as well as RAD26 are much more UV sensitive than cells lacking only the GG-NER gene.
“Indeed, cells lacking one of these GG-NER genes as well as RAD26 are much more UV sensitive than cells lacking only the GG-NER gene (59).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [59] Verhage, R. A., A. J. van Gool, N. de Groot, J. H. Hoeijmakers, P. van de Putte, and J. Brouwer. 1996. Double mutants of Saccharomyces cerevisiae with alterations in global genome and transcription-coupled repair. Mol. Cell. Biol. 16:496-502. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationcitation§ DISCUSSION
The role of the DNA damage checkpoint in GG-NER appears to rely primarily on induction of repair factors.
“the role of the DNA damage checkpoint in GG-NER appears to rely primarily on induction of repair factors, which is in agreement with previously published work (5)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] Al-Moghrabi, N. M., I. S. Al-Sharif, and A. Aboussekhra. 2003. UV-induced de novo protein synthesis enhances nucleotide excision repair efficiency in a transcription-dependent manner in S. cerevisiae. DNA Repair (Amst.) 2:1185-1197. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ RESULTS
Expression of a phosphorylation-mimicking mutant of Rad26 is not sufficient to bypass the requirement for Mec1.
“showing that expression of a phosphorylation-mimicking mutant of Rad26 is not sufficient to bypass the requirement for Mec1 (Fig. 5C).”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
Damage-induced phosphorylation of Rad26 by the Mec1 kinase enhances the rate of TC-NER.
“Together, these results indicate that damage-induced phosphorylation of Rad26 by the Mec1 kinase enhances the rate of TC-NER.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
Other characteristics than rate of DNA repair must be of greater importance once a certain level of repair impairment has been reached.
“other characteristics than rate of DNA repair must be of greater importance once a certain level of repair impairment has been reached.”
Quote in the paperNot a substantial claim - Interpretationown data§ RESULTS
S27 is the only phosphorylated residue in Rad26.
“Mutation of Rad26 serine 27 abolished the 4NQO-induced shift, whereas all the other single point mutants behaved like the wild-type protein (Fig. 4B, compare lane 4 with lanes 2, 6, 8, 10, and 12, respectively), suggesting that S27 is the only phosphorylated residue in Rad26.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
S27 is the only functionally important Mec1 phosphorylation site.
“In further support of the conclusion that S27 is the only functionally important Mec1 phosphorylation site, the rates of TC-NER in a rad26 mutant in which all 5 SQ/TQ sites were mutated to alanine and one in which S27/S29/S30 were mutated together were similar to that of the rad26S27A mutant (data not shown).”
Quote in the paperSubstantial claim- Rests on an assumption: S27 is part of an SQ motif, the general consensus recognition motif for Mec1 and Tel1 kinases.
- Interpretationown data§ DISCUSSION
Additional phosphorylation events on one or more other factors, carried out by one or more kinases in the DDC, appear to also be required for efficient TC-NER.
“Thus, additional phosphorylation events on one or more other factors, carried out by one or more kinases in the DDC, appear to also be required for efficient TC-NER.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
Cellular characteristics other than the rate of TC-NER repair are important for cell survival after UV irradiation.
“This result indicates that cellular characteristics other than the rate of TC-NER repair are important for cell survival after UV irradiation”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
Phosphorylation of S27 may occasionally result in modification of S29 and/or S30.
“Together, these data indicate that Mec1 phosphorylates S27 of Rad26 after DNA damage and that this event may also occasionally result in modification of S29 and/or S30 as well.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ RESULTS
The defect in TC-NER in the checkpoint-deficient strain must be caused by a preexisting factor or factors.
“Together, these results are consistent with the idea that the defect in GG-NER observed in the checkpoint-deficient strain is due to defects in induced expression of factors required for dealing with DNA damage, while the defect in TC-NER must be caused by a preexisting factor(s).”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
Mec1 phosphorylates S27 of Rad26 after DNA damage.
“Together, these data indicate that Mec1 phosphorylates S27 of Rad26 after DNA damage and that this event may also occasionally result in modification of S29 and/or S30 as well.”
Quote in the paperSubstantial claim- Rests on an assumption: S27 is part of an SQ motif, the general consensus recognition motif for Mec1 and Tel1 kinases.
- Interpretationown data§ DISCUSSION
The checkpoint appears to function in TC-NER primarily via modification of repair factors.
“In contrast, the checkpoint appears to function in TC-NER primarily via modification of repair factors, since inhibition of new protein synthesis via cycloheximide treatment had little or no effect on this repair pathway.”
Quote in the paperSubstantial claim- Rests on an assumption: Cycloheximide treatment inhibits new protein synthesis.
- Interpretationown data§ RESULTS
Phosphorylation of Rad26 is not absolutely required for the function of the protein in repair.
“These results indicate that phosphorylation of Rad26 is not absolutely required for the function of the protein in repair but did not rule out the possibility that the modification has an effect on TC-NER kinetics that is not severe enough to cause altered sensitivity to UV light in phenotypic assays.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
Mutation of serine 27 to glutamate indeed acts as a phosphomimic.
“indicating that mutation of serine 27 to glutamate indeed acts as a phosphomimic.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
Slower kinetics of TC-NER do not necessarily result in increased sensitivity to UV irradiation.
“reinforces the idea that slower kinetics of TC-NER do not necessarily result in increased sensitivity to UV irradiation, as observed previously with the rad26SA mutant.”
- Also stated in: § DISCUSSION · plain
“showing that a decrease in TC-NER kinetics does not necessarily lead to a an increase in UV sensitivity.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Interpretationown data§ RESULTS
More than one phosphate group can be added to Rad26 after DNA damage.
“suggesting that more than one phosphate group can be added to Rad26 after DNA damage.”
Quote in the paperSubstantial claim - Interpretationcitation§ DISCUSSION
The severe symptoms of CS patients are almost certainly not due to persistence of NER lesions in the transcribed strand of active genes.
“it is almost certainly not due to persistence of NER lesions in the transcribed strand of active genes, as these lesions also persist in several classes of XP patients (XPA, XPD, XPB, XPF, and XPG) who do not display these severe symptoms (10).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] de Boer, J., and J. H. Hoeijmakers. 2000. Nucleotide excision repair and human syndromes. Carcinogenesis 21:453-460. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- Study design and conductnone given§ RESULTS
The MHRAD26-tagged Rad26 protein is fully functional in TC-NER.
“Genetic characterization of the strain indicated that this protein is fully functional in TC-NER (data not shown).”
Quote in the paperNot a substantial claim - Interpretationown data§ DISCUSSION
The increase in repair efficiency observed when S27 is phosphorylated is not enough to affect viability after DNA damage.
“This indicates that the increase in repair efficiency observed when S27 is phosphorylated is not enough to affect viability after DNA damage.”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
Mutating the phosphorylation site in Rad26 to alanine does not further diminish TC-NER if the strain already lacks the responsible Mec1 kinase.
“showing that, as expected, mutating the phosphorylation site in Rad26 to alanine does not further diminish TC-NER if the strain already lacks the responsible Mec1 kinase.”
Quote in the paperSubstantial claim - Premisecitation§ RESULTS
S27 and S29 of Rad26 are phosphorylated in a Mec1-dependent manner.
“a proteome-wide study of protein phosphorylation reported that S27 and S29 of Rad26 are phosphorylated in a Mec1-dependent manner (4).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Albuquerque, C. P., M. B. Smolka, S. H. Payne, V. Bafna, J. Eng, and H. Zhou. 2008. A multidimensional chromatography technology for in-depth phosphoproteome analysis. Mol. Cell. Proteomics 7:1389-1396. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- Interpretationown data§ RESULTS
The kinase activity of Mec1 is required for Rad26 phosphorylation.
“This indicates that the kinase activity of Mec1 is required for Rad26 phosphorylation.”
Quote in the paperSubstantial claim- Rests on an assumption: MEC1kd is a kinase-dead form of Mec1.
- May combine two claims. 24
- Classified as probably not a substantial claim. 19
May combine two claims.
Findingown data§ RESULTSIn wild-type yeast, CHX treatment does not detectably affect TS repair but causes severely defective NTS repair similar to that observed in the mec1Δ sml1Δ strain.
“Repair of the TS was not detectably affected by CHX treatment, while severely defective NTS repair was observed, similar to that observed in the mec1Δ sml1Δ strain (Fig. 1C).”
Quote in the paperSubstantial claim- Rests on an assumption: Cycloheximide treatment abolishes synthesis of new proteins.
May combine two claims.
Findingown data§ RESULTSIn mec1Δ sml1Δ cells, repair of the TS is markedly slower and repair of the NTS is virtually absent at 4 h post-UV irradiation.
“Interestingly, cells lacking the checkpoint kinase Mec1 exhibited a dramatic impairment of NER, characterized by markedly slower repair of the TS and virtually no repair of the NTS at 4 h post-UV irradiation.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESULTSIn wild-type cells, the difference in repair kinetics between the preferentially repaired TS and the NTS was evident, while no clear strand specificity was observed in TC-NER-deficient rad26Δ cells.
“As expected, the difference in repair kinetics between the preferentially repaired TS and the NTS was evident in the WT strain, while no clear strand specificity was observed in TC-NER-deficient rad26Δ cells.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ DISCUSSIONFew proteins associate stably with Rad26 so that they can be identified by MS analysis.
“in our hands, few proteins associate stably with Rad26 so that they can be identified by MS analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Findingnone given§ DISCUSSIONOther preliminary data suggest that more sites in CSB may also be phosphorylated.
“other preliminary data suggest that more sites in CSB may also be phosphorylated”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ DISCUSSIONRepair of both strands of an active gene is defective in cells lacking Mec1 but not in cells lacking Rad53 and Chk1.
“Our data indicate that repair of both strands of an active gene is defective in cells lacking Mec1 but not in cells lacking Rad53 and Chk1”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESULTSRad26 phosphorylation is recovered by wild-type MEC1 but not by kinase-dead MEC1, despite similar expression.
“Rad26 phosphorylation was recovered by growing cells carrying MEC1wt in galactose, but not glucose, while MEC1kd was unable to generate modified Rad26 despite being expressed at a level similar to the wild-type protein (Fig. 3B, compare lanes 3 and 4 with lanes 7 and 8).”
Quote in the paperSubstantial claim- Rests on an assumption: MEC1kd is a kinase-dead form of Mec1.
May combine two claims.
Findingown data§ RESULTSRad26 possesses 1 TQ and 4 SQ consensus motifs.
“Rad26 possesses 1 TQ and 4 SQ consensus motifs (Fig. 4A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ DISCUSSIONThe delay in TC-NER caused by the rad26SA mutation is most evident shortly after DNA damage induction, which correlates well with the rapid phosphorylation of Rad26 observed in response to UV irradiation.
“This delay is most evident shortly after DNA damage induction, which correlates well with the rapid phosphorylation of Rad26 observed in response to UV irradiation.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ DISCUSSIONRad26 phosphorylation required Mec1, but not Rad53, Chk1, Tel1, or Dun1.
“Rad26 phosphorylation required Mec1, but not Rad53, Chk1, Tel1, or Dun1.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESULTSMutation of Rad26 serine 27 to alanine abolishes the 4NQO-induced mobility shift, whereas all other single point mutants behave like the wild-type protein.
“Mutation of Rad26 serine 27 abolished the 4NQO-induced shift, whereas all the other single point mutants behaved like the wild-type protein (Fig. 4B, compare lane 4 with lanes 2, 6, 8, 10, and 12, respectively), suggesting that S27 is the only phosphorylated residue in Rad26.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESULTSDamage-induced Rad26 phosphorylation is abrogated only in cells lacking Mec1, not in cells lacking Chk1, Rad53, Tel1, or Dun1.
“Damage-induced phosphorylation was abrogated only in cells lacking the Mec1 kinase, supporting the idea that Mec1 directly phosphorylates Rad26 without the involvement of downstream kinases (Fig. 3C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESULTSAfter UV-C irradiation, a slower-migrating form of Rad26 becomes evident at 10 min, peaks between 1 and 2 h, and then starts disappearing.
“Interestingly, a slower-migrating form of the Rad26 protein became evident just 10 min after UV treatment, peaked between 1 and 2 h, and started disappearing thereafter (Fig. 2A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESULTSRAD26 deletion had little effect or appeared to slightly suppress the UV sensitivity of the mec1Δ sml1Δ strain at high UV doses.
“As a matter of fact, RAD26 deletion had little effect or appeared to slightly suppress the UV sensitivity of the mec1Δ sml1Δ strain at high UV doses.”
- Also stated in: § DISCUSSION · plain
“no significant increase in UV sensitivity was observed in the mec1Δ sml1Δ rad26Δ strain”
Quote in the paperSubstantial claim- Also stated in: § DISCUSSION · plain
May combine two claims.
Findingown data§ RESULTSHeat shock and osmotic shock do not result in Rad26 phosphorylation.
“Interestingly, other forms of cellular stress, including heat shock and osmotic shock, did not result in such modification (Fig. 2D).”
Quote in the paperSubstantial claim- Rests on an assumption: Heat shock and osmotic shock do not cause DNA damage.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ AbstractMany of the DNA-damage-upregulated genes are regulated by Mec1, indicating involvement of the DNA damage checkpoint in the DNA damage-related transcriptional response.
“Many of these genes are regulated by Mec1, indicating an involvement of the DNA damage checkpoint in the DNA damage-related transcriptional response (15).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Gasch, A. P., M. Huang, S. Metzner, D. Botstein, S. J. Elledge, and P. O. Brown. 2001. Genomic expression responses to DNA-damaging agents and the regulatory role of the yeast ATR homolog Mec1p. Mol. Biol. Cell 12:2987-3003. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ AbstractMec1 controls the checkpoint by direct phosphorylation of target proteins and also via phosphorylation of downstream effector kinases, most notably Rad53 and Chk1.
“Mec1 controls the checkpoint by direct phosphorylation of target proteins but also via phosphorylation of downstream effector kinases, most notably the kinases Rad53 and Chk1 (11, 43, 49).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [11] de la Torre-Ruiz, M. A., C. M. Green, and N. F. Lowndes. 1998. RAD9 and RAD24 define two additive, interacting branches of the DNA damage checkpoint pathway in budding yeast normally required for Rad53 modification and activation. EMBO J. 17:2687-2698. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [43] Sanchez, Y., B. A. Desany, W. J. Jones, Q. Liu, B. Wang, and S. J. Elledge. 1996. Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways. Science 271:357-360. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [49] Sun, Z., D. S. Fay, F. Marini, M. Foiani, and D. F. Stern. 1996. Spk1/Rad53 is regulated by Mec1-dependent protein phosphorylation in DNA replication and damage checkpoint pathways. Genes Dev. 10:395-406. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ AbstractTwo subpathways of NER exist: transcription-blocking lesions in the transcribed strand of active genes are repaired quickly by transcription-coupled NER, whereas the rest of the genome, including the nontranscribed strand of active genes, is repaired more slowly by global genome NER.
“Two subpathways of NER exist: transcription-blocking lesions in the transcribed strand (TS) of active genes are repaired quickly by transcription-coupled NER (TC-NER), whereas the rest of the genome, including the nontranscribed strand (NTS) of active genes, is repaired more slowly by global genome NER (GG-NER) (8, 33, 34, 44, 54).”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [8] Bohr, V. A., C. A. Smith, D. S. Okumoto, and P. C. Hanawalt. 1985. DNA repair in an active gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall. Cell 40:359-369. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [33] Mellon, I., V. A. Bohr, C. A. Smith, and P. C. Hanawalt. 1986. Preferential DNA repair of an active gene in human cells. Proc. Natl. Acad. Sci. U. S. A. 83:8878-8882. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [34] Mellon, I., G. Spivak, and P. C. Hanawalt. 1987. Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene. Cell 51:241-249. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [44] Selby, C. P., E. M. Witkin, and A. Sancar. 1991. Escherichia coli mfd mutant deficient in “mutation frequency decline” lacks strand-specific repair: in vitro complementation with purified coupling factor. Proc. Natl. Acad. Sci. U. S. A. 88:11574-11578. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [54] Terleth, C., C. A. van Sluis, and P. van de Putte. 1989. Differential repair of UV damage in Saccharomyces cerevisiae. Nucleic Acids Res. 17:4433-4439. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ AbstractDamage detection in TC-NER is carried out by elongating RNA polymerase II itself.
“Damage detection in TC-NER is carried out by elongating RNA polymerase II (RNAPII) itself (reviewed in reference 50).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Svejstrup, J. Q. 2002. Mechanisms of transcription-coupled DNA repair. Nat. Rev. Mol. Cell Biol. 3:21-29. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ AbstractIn Saccharomyces cerevisiae, Mec1 protein kinase is the most important component of the damage checkpoint and is the yeast homologue of human ATR.
“In Saccharomyces cerevisiae, the most important of these is the Mec1 protein kinase, the yeast homologue of human ATR (26, 39, 45).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [26] Kato, R., and H. Ogawa. 1994. An essential gene, ESR1, is required for mitotic cell growth, DNA repair and meiotic recombination in Saccharomyces cerevisiae. Nucleic Acids Res. 22:3104-3112. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [39] Paulovich, A. G., and L. H. Hartwell. 1995. A checkpoint regulates the rate of progression through S phase in S. cerevisiae in response to DNA damage. Cell 82:841-847. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [45] Siede, W., J. B. Allen, S. J. Elledge, and E. C. Friedberg. 1996. The Saccharomyces cerevisiae MEC1 gene, which encodes a homolog of the human ATM gene product, is required for G1 arrest following radiation treatment. J. Bacteriol. 178:5841-5843. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Premisecitation§ AbstractRad26 is the Saccharomyces cerevisiae homologue of CSB, was cloned based on sequence similarity, and is required for normal TC-NER.
“The Saccharomyces cerevisiae homologue of CSB, Rad26, was cloned based on sequence similarity and is required for normal TC-NER (58).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [58] van Gool, A. J., R. Verhage, S. M. Swagemakers, P. van de Putte, J. Brouwer, C. Troelstra, D. Bootsma, and J. H. Hoeijmakers. 1994. RAD26, the functional S. cerevisiae homolog of the Cockayne syndrome B gene ERCC6. EMBO J. 13:5361-5369. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ AbstractRad55 and Nej1 are examples of repair proteins phosphorylated by checkpoint kinases in budding yeast, and their modification leads to enhanced repair of double-strand breaks.
“Examples of repair proteins that are phosphorylated by checkpoint kinases in budding yeast include Rad55 and Nej1 (3, 21), modification of which leads to enhanced repair of double-strand breaks.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [3] Ahnesorg, P., and S. P. Jackson. 2007. The non-homologous end-joining protein Nej1p is a target of the DNA damage checkpoint. DNA Repair (Amst.) 6:190-201. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [21] Herzberg, K., V. I. Bashkirov, M. Rolfsmeier, E. Haghnazari, W. H. McDonald, S. Anderson, E. V. Bashkirova, J. R. Yates III, and W. D. Heyer. 2006. Phosphorylation of Rad55 on serines 2, 8, and 14 is required for efficient homologous recombination in the recovery of stalled replication forks. Mol. Cell. Biol. 26:8396-8409. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ AbstractApproximately 5% of the yeast genome is upregulated in response to various DNA-damaging agents.
“Indeed, approximately 5% of the yeast genome is upregulated in response to various DNA-damaging agents (15, 23, 24).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [15] Gasch, A. P., M. Huang, S. Metzner, D. Botstein, S. J. Elledge, and P. O. Brown. 2001. Genomic expression responses to DNA-damaging agents and the regulatory role of the yeast ATR homolog Mec1p. Mol. Biol. Cell 12:2987-3003. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [23] Jelinsky, S. A., P. Estep, G. M. Church, and L. D. Samson. 2000. Regulatory networks revealed by transcriptional profiling of damaged Saccharomyces cerevisiae cells: Rpn4 links base excision repair with proteasomes. Mol. Cell. Biol. 20:8157-8167. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [24] Jelinsky, S. A., and L. D. Samson. 1999. Global response of Saccharomyces cerevisiae to an alkylating agent. Proc. Natl. Acad. Sci. U. S. A. 96:1486-1491. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Interpretationown data§ RESULTSA normal DNA damage checkpoint, and more specifically the Mec1 kinase, is required for efficient repair by both NER subpathways.
“Together, these results indicate that a normal DNA damage checkpoint, and more specifically the Mec1 kinase, is required for efficient repair by both NER subpathways.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ AbstractBudding yeast has a second TC-NER pathway that is dependent on Rpb9, a nonessential subunit of RNAPII.
“In addition, budding yeast has a second TC-NER pathway, which is dependent on Rpb9, a nonessential subunit of RNAPII (29).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Li, S., and M. J. Smerdon. 2002. Rpb4 and Rpb9 mediate subpathways of transcription-coupled DNA repair in Saccharomyces cerevisiae. EMBO J. 21:5921-5929. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning§ DISCUSSIONThese similarities are at least consistent with a link between the DNA damage checkpoint and TC-NER also in humans.
“Although other possibilities cannot be ruled out, these similarities are at least consistent with a link between the DNA damage checkpoint and TC-NER also in humans.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONOne of the CSB SQ/TQ motifs was recently identified as a target for ATM/ATR.
“one of these was recently identified as a target for ATM/ATR (32).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Matsuoka, S., B. A. Ballif, A. Smogorzewska, E. R. McDonald III, K. E. Hurov, J. Luo, C. E. Bakalarski, Z. Zhao, N. Solimini, Y. Lerenthal, Y. Shiloh, S. P. Gygi, and S. J. Elledge. 2007. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316:1160-1166. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ DISCUSSIONClinical features of patients suffering from Seckel syndrome and Cockayne syndrome are overlapping, with both diseases resulting in microencephaly, 'birdlike' facial features, and severe growth defects.
“some of the clinical features of patients suffering from Seckel syndrome (which involves deficiencies in the DNA damage checkpoint [27]) and Cockayne syndrome are overlapping, with both diseases resulting in microencephaly, “birdlike” facial features, and severe growth defects (13, 20).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [13] Falik-Zaccai, T. C., M. Laskar, N. Kfir, W. Nasser, H. Slor, and M. Khayat. 2008. Cockayne syndrome type II in a Druze isolate in Northern Israel in association with an insertion mutation in ERCC6. Am. J. Med. Genet. A 146A:1423-1429. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [20] Harper, R. G., E. Orti, and R. K. Baker. 1967. Bird-beaded dwarfs (Seckel's syndrome). A familial pattern of developmental, dental, skeletal, genital, and central nervous system anomalies. J. Pediatr. 70:799-804. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONMammalian cells lacking CSB are UV sensitive.
“mammalian cells lacking CSB are UV sensitive (56)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [56] Troelstra, C., A. van Gool, J. de Wit, W. Vermeulen, D. Bootsma, and J. H. Hoeijmakers. 1992. ERCC6, a member of a subfamily of putative helicases, is involved in Cockayne's syndrome and preferential repair of active genes. Cell 71:939-953. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONProlonged stalling of RNAPII at sites of DNA damage is a strong signal for apoptosis.
“Prolonged stalling of RNAPII at sites of DNA damage is a strong signal for apoptosis (30)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Ljungman, M., and F. Zhang. 1996. Blockage of RNA polymerase as a possible trigger for u.v. light-induced apoptosis. Oncogene 13:823-831. [PubMed] [Google Scholar]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning§ DISCUSSIONProlonged stalling of RNAPII at sites of DNA damage would be particularly detrimental in the brain, where cells cannot be replaced.
“which would be particularly detrimental in the brain, where cells cannot be replaced.”
Quote in the paperNot a substantial claim- Rests on an assumption: Cells in the brain cannot be replaced.
Classified as probably not a substantial claim.
Premisecitation§ RESULTSMec1 phosphorylates serine and threonine residues that are immediately adjacent to a glutamine (SQ/TQ motifs).
“Mec1 phosphorylates serine and threonine residues that are immediately adjacent to a glutamine (SQ/TQ motifs) (14).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Friedel, A. M., B. L. Pike, and S. M. Gasser. 2009. ATR/Mec1: coordinating fork stability and repair. Curr. Opin. Cell Biol. 21:237-244. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONYeast cells lacking RAD26 are not UV sensitive.
“while yeast cells lacking RAD26 are not (58).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [58] van Gool, A. J., R. Verhage, S. M. Swagemakers, P. van de Putte, J. Brouwer, C. Troelstra, D. Bootsma, and J. H. Hoeijmakers. 1994. RAD26, the functional S. cerevisiae homolog of the Cockayne syndrome B gene ERCC6. EMBO J. 13:5361-5369. [DOI] [PMC free article] [PubMed] [Google Scholar] source
Not checked in the free run.
May combine two claims.
Interpretationown data§ RESULTSRad26 modification is not a result of RNAPII stalling but rather represents a response to DNA damage.
“suggesting that Rad26 modification is not a result of RNAPII stalling but rather represents a response to DNA damage.”
Quote in the paperSubstantial claim- Rests on an assumption: 6-azauracil causes frequent RNAPII stalling by restricting nucleotide availability.
May combine two claims.
Interpretationreasoning§ DISCUSSIONThe effect of mutating Mec1 is via decreased Rad26 phosphorylation (and possibly decreased phosphorylation of other repair factors) rather than of defects in cell cycle progression.
“indicating that the effect of mutating this kinase is via decreased Rad26 phosphorylation (and possibly decreased phosphorylation of other repair factors) rather than of defects in cell cycle progression.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ DISCUSSIONThe DDC-and specifically Mec1-affects both TC-NER and GG-NER.
“indicating that the DDC—and specifically Mec1—affects both TC-NER and GG-NER.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ RESULTSMec1 directly phosphorylates Rad26 without involvement of downstream kinases.
“Damage-induced phosphorylation was abrogated only in cells lacking the Mec1 kinase, supporting the idea that Mec1 directly phosphorylates Rad26 without the involvement of downstream kinases (Fig. 3C).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisecitation§ RESULTSDeletion of SML1 is necessary to suppress the lethality of MEC1 deletion.
“a mec1Δ sml1Δ double mutant strain (deletion of SML1 is necessary to suppress the lethality of MEC1 deletion [66])”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [66] Zhao, X., E. G. Muller, and R. Rothstein. 1998. A suppressor of two essential checkpoint genes identifies a novel protein that negatively affects dNTP pools. Mol. Cell 2:329-340. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
The paper relies on this without support.
Cycloheximide treatment abolishes synthesis of new proteins.
“we carried out NER assays on wild-type yeast treated with cycloheximide (CHX) (in order to abolish synthesis of new proteins) 1 h before UV treatment.”
The paper relies on this without support.
6-azauracil causes frequent RNAPII stalling by restricting nucleotide availability.
“6AU causes frequent RNAPII stalling by restricting nucleotide availability”
The paper relies on this without support.
Heat shock and osmotic shock do not cause DNA damage.
“other forms of cellular stress, including heat shock and osmotic shock, did not result in such modification”
The paper relies on this without support.
The DNA damage checkpoint may enhance the repair capacity of cells.
“it is widely accepted, but rarely demonstrated, that the checkpoint may also enhance the repair capacity of cells.”
The paper relies on this without support.
MEC1kd is a kinase-dead form of Mec1.
“kinase-dead MEC1 (MEC1kd)”
The paper relies on this without support.
S27 is part of an SQ motif, the general consensus recognition motif for Mec1 and Tel1 kinases.
“part of an SQ motif, which is also the general consensus recognition motif for Mec1 and Tel1 kinases.”
The paper relies on this without support.
MEC1 deletion affects NER.
“Given that MEC1 deletion affects NER and that Rad26 appears to be a direct target of the Mec1 kinase, we asked whether Rad26 phosphorylation plays a role in TC-NER.”
The paper relies on this without support.
CSB has numerous potential SQ/TQ motifs.
“we note that CSB has numerous potential SQ/TQ motifs”
The paper relies on this without support.
Oxygen consumption in the brain is much higher than that of any other tissue, resulting in high levels of harmful metabolic by-products, including reactive oxygen species.
“since oxygen consumption in the brain is much higher than that of any other tissue, which in turn results in high levels of harmful metabolic by-products, including reactive oxygen species”
The paper relies on this without support.
Cells in the brain cannot be replaced.
“where cells cannot be replaced.”
The paper relies on this without support.
Cycloheximide treatment inhibits new protein synthesis.
“since inhibition of new protein synthesis via cycloheximide treatment had little or no effect on this repair pathway.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Rad26, critical for TC-NER, is a direct target of Mec1 kinase, and its phosphorylation enhances TC-NER, possibly by stimulating ATPase activity or modulating interactions with other TC-NER proteins.
“Along similar lines, Rad26, a NER factor critical for TC-NER, is a direct target of Mec1 kinase and its phosphorylation enhances TC-NER, possibly by stimulating its ATPase activity or by modulating its interaction with other TC-NER proteins [99].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [99]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
W303 can1 allele differs between methods and Table 1
MinorThe methods identify the W303 background as carrying can1-1, whereas Table 1 lists the W303 strains as carrying can1-100.
“All the Saccharomyces cerevisiae strains used were congenic with strain W303 (leu2-3,112 his3-11,15 ade2-1 ura3-1 trp1-1 can1-1) (55)”
“W303 1A MAT a leu2-3,112 his3-11,15 ade2-1 ura3-1 trp1-1 can1-100 W303 1B MAT α leu2-3,112 his3-11,15 ade2-1 ura3-1 trp1-1 can1-100”
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Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- 10.1101/sqb.2000.65.201 · DOI
Cited by
Sorted by citations
DNA damage kinase signaling: checkpoint and repair at 30 years
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“In budding yeast, Mec1 phosphorylates the nucleotide excision repair (NER) protein Rad26 and regulates the transcription-coupled NER mode of repair (Taschner et al , 2010).”
DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces cerevisiae
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“The cells were grown and manipulated using standard techniques (38).”
MethodSelf-citationRad26p regulates the occupancy of histone H2A–H2B dimer at the active genes in vivo
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“reflecting inhibition of both TC-NER and GG-NER, respectively) (20).”
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“The haploid yeast strains employed are described in detail in the various publications cited in each of the results sections [7–20,33].”
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“Rad26 linked to RNA polymerase II has ATPase activity needed for TC-NER and the bypass of DNA damage [38,39], and its phosphorylation can increase the TC-NER rate of DNA damage [40].”
BackgroundRegulation of active genome integrity and expression by Rad26p
Malik, S., & Bhaumik, S. R. (2014) · Nucleus · doi:10.4161/nucl.36230 · Cited by 2 · see citing works
“Moreover, chromatin remodeling activity of CSB has been implicated in TC-NER.”
BackgroundInfluential(2010) · Yeast · doi:10.1002/yea.1718
Rescue of DNA damage-stalled RNA Pol II: histone H2B in action
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- Authors
- Taschner, M., Harreman, M., Teng, Y., Gill, H., Anindya, R., Maslen, S. L., Skehel, J. M., Waters, R., & Svejstrup, J. Q.
- Affiliations
- Cancer Research UK (GB)
- Cardiff University (GB)
- Protein Analysis and Proteomics Laboratory, Clare Hall Laboratories, Cancer Research UK London Research Institute, Blanche Lane, South Mimms
- Corresponding author
- Svejstrup, Jesper Q.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2010-01
- Volume
- 30
- Issue
- 2
- Pages
- 436-446
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2798469
- OpenAlex
- W2152759034
- Cited by
- 19
- References
- 68
- Citations by year
- 2024: 2 · 2023: 1 · 2019: 1 · 2016: 1 · 2015: 4 · 2014: 2 · 2013: 2 · 2012: 2
- FWCI
- 0.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Funders
- Cancer Research Wales
- Cancer Research UK (11567)
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- transcription-coupled repair, nucleotide excision repair, Mec1 kinase, DNA damage checkpoint, global genome repair, Rad53, Chk1, Tel1, Dun1, Saccharomyces cerevisiae
- MeSH terms
- Adenosine Triphosphatases, DNA Damage, DNA Repair, Mutation, Phosphorylation, Saccharomyces cerevisiae, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Saccharomyces cerevisiae Proteins, Intracellular Signaling Peptides and Proteins, Checkpoint Kinase 2
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