DNA damage checkpoint control in cells exposed to ionizing radiation

Iliakis, George; Wang, Ya; Guan, Jun; Wang, Huichen

doi:10.1038/sj.onc.1206682

Cited by 418 publications

(314 citation statements)

References 225 publications

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“…3F). From the same reason, it seems unlikely that Chk2-dependent transient delay of S phase entry at early times after IR affects dicentric frequency [8][9][10]. Based on the results in Fig.…”

Section: Atm/p53-dependent G1 Checkpoint Contributes To Suppression Omentioning

confidence: 90%

“…To dissect ATM's checkpoint role in suppression of dicentric frequency, we examined the effect of RNAi-mediated knockdown of p53, because p53 is a critical downstream effector of ATM to induce and sustain G1 checkpoint after IR [8,9]. Indeed, p53 shRNA blocked 2 Gy-induced G1 arrest similarly to ATM inhibitor (cf.…”

Section: Atm/p53-dependent G1 Checkpoint Contributes To Suppression Omentioning

confidence: 99%

“…In G1 checkpoint, ATM transduces DSB signals to Chk2 and p53 by phosphorylation, and induces transient delay of S phase entry at earlier times and more sustained blockage of S phase entry at later times, respectively [8][9][10]. In intra-S checkpoint, Chk1, in cooperation with ATM-activated Chk2, is involved in phosphorylation and subsequent degradation of cdc25A, a phosphatase that dephosphorylates and activates cyclin-dependent kinase 2 (cdk2) [8,9]. There is another the probes were predenatured at 72 ˚C for ≥30 min in thermal cycler.…”

Section: Introductionmentioning

confidence: 99%

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Mode of ATM-dependent suppression of chromosome translocation

Yamauchi

Suzuki

Oka

et al. 2011

Biochemical and Biophysical Research Communications

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It is well documented that deficiency in ataxia telangiectasia mutated (ATM) protein leads to elevated frequency of chromosome translocation, however, it remains poorly understood how ATM suppresses translocation frequency. In the present study, we addressed the mechanism of ATM-dependent suppression of translocation frequency. To know frequency of translocation events in a whole genome at once, we performed centromere/telomere FISH and scored dicentric chromosomes, because dicentric and translocation occur with equal frequency and by identical mechanism. By centromere/telomere FISH analysis, we confirmed that chemical inhibition orRNAi-mediated knockdown of ATM causes 2~2.5-fold increase in dicentric frequency at first mitosis after 2 Gy of gamma-irradiation in G0/G1. The FISH analysis revealed that ATM/p53-dependent G1 checkpoint suppresses dicentric frequency, since RNAi-mediated knockdown of p53 elevated dicentric frequency by 1.5-fold. We found ATM also suppresses dicentric occurrence independently of its checkpoint role, as ATM inhibitor showed additional effect on dicentric frequency in the context of p53 depletion and Chk1/2 inactivation. Epistasis analysis using chemical inhibitors revealed that ATM kinase functions in the same pathway that requires kinase activity of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress dicentric frequency. From the results in the present study, we conclude that ATM minimizes translocation frequency through its commitment to G1 checkpoint and DNA double-strand break repair pathway that requires kinase activity of DNA-PKcs.

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Section: Atm/p53-dependent G1 Checkpoint Contributes To Suppression Omentioning

confidence: 90%

Section: Atm/p53-dependent G1 Checkpoint Contributes To Suppression Omentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mode of ATM-dependent suppression of chromosome translocation

Yamauchi

Suzuki

Oka

et al. 2011

Biochemical and Biophysical Research Communications

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“…An early and transient G 2 arrest is considered to be ATM dependent (Xu et al, 2002). A second G 2 arrest, which occurs later in response to irradiation caused in the earlier phases of the cell cycle, is independent of ATM (Iliakis et al, 2003). E2F4 is a good candidate for regulating this second, sustained G 2 arrest, as depletion of ATM by siRNA-mediated knockdown had no effect on this radiation-induced G 2 arrest (S Ray et al, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma

et al. 2006

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The retinoblastoma (pRB) family proteins regulate the E2F transcription factors; their complexes regulate critical transitions through the cell cycle. The function of these pRB family/E2F complexes, which includes p130/ E2F4, in response to genotoxic agents, is not well understood. We investigated the role of E2F4 in the genotoxic stress response. Following radiation treatment, E2F4 colocalized with p130 in the nucleus during a radiation-induced stable G 2 -phase arrest. Arrested cells had significantly decreased expression of Cyclins A2 and B1 and decreased phosphorylation of mitotic protein monoclonal-2 (MPM-2) mitotic proteins. Small interference RNA (siRNA)-mediated knockdown of E2F4 sensitized cells to subsequent irradiation, resulting in enhanced cellular DNA damage and cell death, as determined by caspase activation and decreased clonogenic cell survival. Downstream E2F4 targets potentially involved in the progression from G 2 into M phase were identified by oligonucleotide microarray expression profiling. Chromatin immunoprecipitation localized E2F4 at promoter regions of the Bub3 and Pttg1 mitotic genes following irradiation, which were among the downregulated genes identified by the microarray. These data suggest that in response to radiation, E2F4 becomes active in the nucleus, enforces a stable G 2 arrest by target gene repression, and thus provides increased cell survival ability by minimizing propagation of cells that have irreparable DNA damage.

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“…Upon sensing the damage signals, ATM and ATR phosphorylate CHK2 on Thr68, which then leads to activation of CHK2. Once activated, CHK2 phosphorylates its downstream targets such as p53, Cdc25 and FOXM1, leading to growth arrest, apoptosis, or DNA repair (Iliakis et al, 2003;Antoni et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The cell cycle checkpoint kinase CHK2 mediates DNA damage-induced stabilization of TTK/hMps1

Huang

Lin

et al. 2009

Oncogene

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Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68. However, it remains to be determined whether and how TTK/hMps1 responds to DNA damage. In this report, we present evidence that TTK/hMps1 can be induced by DNA damage in normal human fibroblasts. Interestingly, the induction depends on CHK2 because CHK2-targeting small interfering RNA or a CHK2 inhibitor abolishes the increase. Such induction is mediated through phosphorylation of TTK/hMps1 at Thr288 by CHK2 and requires the CHK2 SQ/TQ cluster domain/forkhead-associated domain. In cells, TTK/ hMps1 phosphorylation at Thr288 is induced by DNA damage and forms nuclear foci, which colocalize partially with c-H2AX. Reexpression of TTK/hMps1 T288A mutant in TTK/hMps1-knockdown cells causes a defect in G 2 /M arrest, suggesting that phosphorylation at this site participates in the proper checkpoint execution. Our study uncovered a regulatory loop between TTK/hMps1 and CHK2 whereby DNA damage-activated CHK2 may facilitate the stabilization of TTK/hMps1, therefore maintaining the checkpoint control.

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DNA damage checkpoint control in cells exposed to ionizing radiation

Cited by 418 publications

References 225 publications

Mode of ATM-dependent suppression of chromosome translocation

Mode of ATM-dependent suppression of chromosome translocation

E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma

The cell cycle checkpoint kinase CHK2 mediates DNA damage-induced stabilization of TTK/hMps1

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