The DNA damage response: putting checkpoints in perspective

Zhou, Bin‐Bing S.; Elledge, Stephen J.

doi:10.1038/35044005

Cited by 2,892 publications

(2,555 citation statements)

References 95 publications

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“…However, our findings were not artifacts, as (1) we have used two specific anti-ATR antibodies, (2) both immunofluorescent as well as cell fractioning experiments confirmed ATR cytosolic localization, (3) the cytosolic localization of ATR was observed in MCF7 (Figures 4c and 8) and NIH3T3 cells (data not shown), and (4) HU exposure abolished the presence of ATR in the cytosol (Figure 8b). Our finding of the cytosolic localization of ATR is consistent with the cytosolic and nuclear localization of ATM (Yang and Kastan, 2000), as ATR and ATM are regarded as functional equivalents in mediating a variety of DNA damage responses (Zhou and Elledge, 2000).…”

Section: Discussionsupporting

confidence: 84%

“…Erk kinase facilitates S-phase DNA damage checkpoint D Wu et al system not only functions in the repair of DNA damage, but also integrates with other cellular processes to regulate cell cycle progression, apoptosis, and transcription (Zhou and Elledge, 2000). Consistent with its involvement in all of these cellular processes, Erk has been reported by several groups, including ours, to function in the DNA damage response (Lee et al, 2000;Persons et al, 2000;Wang et al, 2000;Tang et al, 2002;Pippin et al, 2003).…”

Section: Discussionsupporting

confidence: 53%

“…PD98059 produced the same results in both cell lines (data not shown). Since gH2AX is recruited onto DNA breaks and functions in DNA damage repair (Zhou and Elledge, 2000), we have examined whether inhibition of Erk activation would affect HU-induced gH2AX nuclear foci. Indeed, both U0126 and PD98059 (data not shown) significantly attenuated HU-induced gH2AX nuclear foci in MCF7 (Figure 5b) and NIH3T3 cells (data not shown).…”

Section: Inhibition Of Erk Activity Sensitizes Cells To Hu Toxicitymentioning

confidence: 99%

“…Critical surveillance of this transmission is provided by the DNA damage response (Zhou and Elledge, 2000). Disruption or attenuation of this response plays an essential role in promoting tumorigenesis (Lengauer et al, 1998;Hoeijmakers, 2001;Schar, 2001;Rouse and Jackson, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Stalled replication forks are sensed by replication protein A (RPA)-mediated ATR (ATM-and Rad3-related kinase) recruitment to DNA damage-induced nuclear foci (Zou and Elledge, 2003). ATR and its related ATM kinases play central roles in the amplification of double-stranded break (DSB) signals, coordination of DNA damage repair and activation of cell cycle checkpoints (Zhou and Elledge, 2000;Shiloh, 2003).…”

Section: Introductionmentioning

confidence: 99%

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ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

Chen

Parihar

et al. 2005

Oncogene

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Although Erk kinase has been recently reported to function in the DNA damage response, the mechanism governing this process is unknown. We report here that hydroxyurea (HU) activates Erk via MEK1, a process that is sensitized by a constitutively active MEK1 (MEK1Q56P) and attenuated by a dominant-negative MEK1 (MEK1K97M). While ectopic MEK1Q56P sensitized HU-induced S-phase arrest, inhibition of Erk activation via U0126, PD98059, and MEK1K97M attenuated the arrest, and thereby enhanced cells to HU-induced toxicity. Taken together, we demonstrate an important contribution of Erk to the activation of the S-phase DNA damage checkpoint. This can be attributed to Erk's regulatory role in modulating ATR function. Inhibition of Erk activation with U0126/PD98059 and MEK1K97M substantially reduced HU-induced ATR nuclear foci, leading to a dramatic reduction of cH2AX and its nuclear foci. Reduction of MEK1 function by a small interference RNA (siRNA) MEK1 and ectopic MEK1K97M significantly decreased HU-induced cH2AX. Conversely, ectopic MEK1Q56P enhanced cH2AX foci. Furthermore, immunofluorescent and cell fractioning experiments revealed cytosolic and nuclear localization of ATR. HU treatment caused the redistribution of ATR from the cytosol to the nucleus, a process that is inhibited by U0126. Collectively, we show that Erk kinase modulates HU-initiated DNA damage response by regulating ATR function.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 53%

Section: Inhibition Of Erk Activity Sensitizes Cells To Hu Toxicitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

Chen

Parihar

et al. 2005

Oncogene

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DNARepair and the Cell Cycle as Targets in Cancer Therapy

Rajewsky

Müller

2005

The Cancer Handbook

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Ribonucleotide Reductase: Recent Advances

Stubbe¹,

Cotruvo²

2004

Handbook of Metalloproteins

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Ribonucleotide reductases (RNRs) catalyze the conversion of nucleotides to deoxynucleotides and play an essential role in nucleic acid metabolism in all organisms. RNRs have been divided into three classes. They share a structurally homologous subunit where the reduction occurs, with the chemistry being initiated by thiyl radical‐mediated abstraction of the nucleotide's 3′‐hydrogen atom. The classification of RNRs is based on the different strategies used to generate the transient thiyl radical. The class Ia and Ib RNRs use a diferric‐tyrosyl radical cofactor, the class II RNRs use adenosylcobalamin, and the class III RNRs use a glycyl radical generated by a [4Fe4S] 1+ cluster and S ‐adenosylmethionine. This article focuses on the recent advances in our understanding of the in vitro and in vivo mechanisms of formation of the metallocofactors in the class I RNRs in E. coli and S. cerevisiae . The discovery of a new class of RNR, class Ic, whose active cofactor is proposed to be an Mn IV Fe III cluster, and a summary of recent insights into the chemistry of the novel cofactor are also described. Finally, the current understanding of the unprecedented role of the metallocofactor in radical propagation over 35 Å in the class Ia—and presumably class Ib and Ic—RNRs is presented.

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The DNA damage response: putting checkpoints in perspective

Cited by 2,892 publications

References 95 publications

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

DNARepair and the Cell Cycle as Targets in Cancer Therapy

Ribonucleotide Reductase: Recent Advances

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