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

Wu, Dongcheng; Chen, B; Parihar, Kavita; He, Lizhi; Fan, Catherine; Zhang, J; Liu, L; Gillis, Aubrey; Bruce, Anthony; Kapoor, Anil; Tang, Damu

doi:10.1038/sj.onc.1209148

Cited by 55 publications

(53 citation statements)

References 49 publications

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“…Etoposide-induced ERK activation was shown to mediate cell cycle arrest in an ATM-dependent but p53-independent manner (47). In the case of other stresses, such as hydroxyurea and ionizing radiation, ERK activation was required for S phase and G 2 /M checkpoint arrest, respectively (48,49). Moreover, Yan et al reported that ionizing radiation-induced ERK1/2 activation required a direct interaction with BRCA1 for G 2 /M cell cycle checkpoint arrest (50).…”

Section: Discussionmentioning

confidence: 99%

Peroxiredoxin II Restrains DNA Damage-induced Death in Cancer Cells by Positively Regulating JNK-dependent DNA Repair

Lee¹,

Lee

Lee³

et al. 2011

Journal of Biological Chemistry

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The 2-Cys peroxiredoxins (Prx) belong to a family of antioxidant enzymes that detoxify reactive oxygen and nitrogen species and are distributed throughout the intracellular and extracellular compartments. However, the presence and role of 2-Cys Prxs in the nucleus have not been studied. This study demonstrates that the PrxII located in the nucleus protects cancer cells from DNA damage-induced cell death. Although the two cytosolic 2-Cys Prxs, PrxI and PrxII, were found in the nucleus, only PrxII knockdown selectively and markedly increased cell death in the cancer cells treated with DNA-damaging agents. The increased death was completely reverted by the nuclearly targeted expression of PrxII in an activity-independent manner. Furthermore, the antioxidant butylated hydroxyanisole did not influence the etoposide-induced cell death. Mechanistically, the knockdown of Prx II expression impaired the DNA repair process by reducing the activation of the JNK/c-Jun pathway. These results suggest that PrxII is likely to be attributed to a tumor survival factor positively regulating JNK-dependent DNA repair with its inhibition possibly sensitizing cancer cells to chemotherapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Peroxiredoxin II Restrains DNA Damage-induced Death in Cancer Cells by Positively Regulating JNK-dependent DNA Repair

Lee¹,

Lee

Lee³

et al. 2011

Journal of Biological Chemistry

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“…break formation in the S phase (47). A similar mechanism could link ERK and ATM perhaps through a feedback loop that might regulate cellular homeostasis and sense the well being of the cell; if DNA damage is repairable, prosurvival ERK signaling might positively influence HRR, whereas overwhelming DNA damage might inhibit ERK signaling and HRR.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Signal-Related Kinase Positively Regulates Ataxia Telangiectasia Mutated, Homologous Recombination Repair, and the DNA Damage Response

et al. 2007

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The accurate joining of DNA double-strand breaks by homologous recombination repair (HRR) is critical to the long-term survival of the cell. The three major mitogenactivated protein (MAP) kinase (MAPK) signaling pathways, extracellular signal-regulated kinase (ERK), p38, and c-Jun-NH 2 -kinase (JNK), regulate cell growth, survival, and apoptosis. To determine the role of MAPK signaling in HRR, we used a human in vivo I-SceI-based repair system. First, we verified that this repair platform is amenable to pharmacologic manipulation and show that the ataxia telangiectasia mutated (ATM) kinase is critical for HRR. The ATM-specific inhibitor KU-55933 compromised HRR up to 90% in growth-arrested cells, whereas this effect was less pronounced in cycling cells. Then, using well-characterized MAPK small-molecule inhibitors, we show that ERK1/2 and JNK signaling are important positive regulators of HRR in growth-arrested cells. On the other hand, inhibition of the p38 MAPK pathway generated an almost 2-fold stimulation of HRR. When ERK1/2 signaling was stimulated by oncogenic RAF-1, an f2-fold increase in HRR was observed. KU-55933 partly blocked radiation-induced ERK1/2 phosphorylation, suggesting that ATM regulates ERK1/2 signaling. Furthermore, inhibition of MAP/ERK kinase (MEK)/ERK signaling resulted in severely reduced levels of phosphorylated (S1981) ATM foci but not ;-H2AX foci, and suppressed ATM phosphorylation levels >85% throughout the cell cycle. Collectively, these results show that MAPK signaling positively and negatively regulates HRR in human cells. More specifically, ATM-dependent signaling through the RAF/MEK/ ERK pathway is critical for efficient HRR and for radiationinduced ATM activation, suggestive of a regulatory feedback loop between ERK and ATM. [Cancer Res 2007;67(3):1046-53]

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“…Of these, CDK1 is unlikely to be required to phosphorylate Ser5 when cells are arrested in S phase because it is only active in the G2/M phase of the cell cycle (Clute and Pines 1999). More likely, either ERK or DNA-PK modifies RNAPII Ser5 after HU, as both kinases have been shown to be activated by S-phase block (Wu et al 2006). Further Figure 8.…”

Section: Discussionmentioning

confidence: 99%

A role for Chk1 in blocking transcriptional elongation of p21 RNA during the S-phase checkpoint

Beckerman¹,

Donner²,

Mattia³

et al. 2009

Genes Dev.

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We reported previously that when cells are arrested in S phase, a subset of p53 target genes fails to be strongly induced despite the presence of high levels of p53. When DNA replication is inhibited, reduced p21 mRNA accumulation is correlated with a marked reduction in transcription elongation. Here we show that ablation of the protein kinase Chk1 rescues the p21 transcription elongation defect when cells are blocked in S phase, as measured by increases in both p21 mRNA levels and the presence of the elongating form of RNA polymerase II (RNAPII) toward the 39 end of the p21 gene. Recruitment of specific elongation and 39 processing factors (DSIF, CstF-64, and CPSF-100) is also restored. While additional components of the RNAPII transcriptional machinery, such as TFIIB and CDK7, are recruited more extensively to the p21 locus after DNA damage than after replication stress, their recruitment is not enhanced by ablation of Chk1. Significantly, ablating Chk2, a kinase closely related in substrate specificity to Chk1, does not rescue p21 mRNA levels during S-phase arrest. Thus, Chk1 has a direct and selective role in the elongation block to p21 observed during S-phase arrest. These findings demonstrate for the first time a link between the replication checkpoint mediated by ATR/Chk1 and the transcription elongation/ 39 processing machinery.[Keywords: Chk1; Chk2; S-phase checkpoint; p53; transcription elongation] Supplemental material is available at http://www.genesdev.org.

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

Cited by 55 publications

References 49 publications

Peroxiredoxin II Restrains DNA Damage-induced Death in Cancer Cells by Positively Regulating JNK-dependent DNA Repair

Peroxiredoxin II Restrains DNA Damage-induced Death in Cancer Cells by Positively Regulating JNK-dependent DNA Repair

Extracellular Signal-Related Kinase Positively Regulates Ataxia Telangiectasia Mutated, Homologous Recombination Repair, and the DNA Damage Response

A role for Chk1 in blocking transcriptional elongation of p21 RNA during the S-phase checkpoint

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