Cell cycle checkpoint signaling through the ATM and ATR kinases

Abraham, Robert T.

doi:10.1101/gad.914401

Cited by 1,833 publications

(1,864 citation statements)

References 142 publications

(187 reference statements)

Supporting

Mentioning

1,805

Contrasting

Unclassified

Order By: Relevance

“…Both ATR and ATM activate Chk1 under conditions that induce fragile site expression ATR and ATM have two major effectors; Chk1 and Chk2 respectively (Abraham, 2001). Recently, Durkin Interplay between ATM and ATR in fragile site regulation E Ozeri-Galai et al et al showed that Chk1 but not Chk2 regulates common fragile site stability ).…”

Section: Resultsmentioning

confidence: 99%

“…The first checkpoint protein implicated in fragile site stability was ataxiatelangiectasia and Rad3-related (ATR). ATR plays a central role in the checkpoint response to agents that block replication fork progression (Abraham, 2001). Downregulation of ATR results in increased instability at fragile site following replication stress, and even under normal growth conditions (Casper et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Interplay between ATM and ATR in the regulation of common fragile site stability

et al. 2007

View full text Add to dashboard Cite

Common fragile sites are specific genomic loci that form constrictions and gaps on metaphase chromosomes under conditions that slow, but do not arrest, DNA replication. These sites have been shown to have a role in various chromosomal rearrangements in tumors. Different DNA damage response proteins were shown to regulate fragile site stability, including ataxia-telangiectasia and Rad3-related (ATR) and its effector Chk1. Here, we investigated the role of ataxia-telangiectasia mutated (ATM), the main transducer of DNA double-strand break (DSB) signal, in this regulation. We demonstrate that replication stress conditions, which induce fragile site expression, lead to DNA fragmentation and recruitment of phosphorylated ATM to nuclear foci at DSBs. We further show that ATM plays a role in maintaining fragile site stability, which is revealed only in the absence of ATR. However, the activation of ATM under these replication stress conditions is ATR independent. Following conditions that induce fragile site expression both ATR and ATM phosphorylate Chk1, suggesting that both proteins regulate fragile site expression probably via their effect on Chk1 activation. Our findings provide new insights into the interplay between ATR and ATM pathways in response to partial replication inhibition and in the regulation of fragile site stability.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interplay between ATM and ATR in the regulation of common fragile site stability

et al. 2007

View full text Add to dashboard Cite

show abstract

“…It is well established that ATM is essential in maintaining G 2 checkpoint function (Terzoudi et al, 2005;Deckbar et al, 2007) through inhibition of cyclin B1/cdc2 (Abraham, 2001). We, therefore, examined the effect of a specific and potent ATM inhibitor, KU55933 (Rainey et al, 2008), which is known as a 'molecular switch' because of its rapid and reversible inactivation of ATM (White et al, 2008), on centromeric instability.…”

Section: Resultsmentioning

confidence: 99%

“…We, therefore, examined the effect of a specific and potent ATM inhibitor, KU55933 (Rainey et al, 2008), which is known as a 'molecular switch' because of its rapid and reversible inactivation of ATM (White et al, 2008), on centromeric instability. Being aware that ATM also has G 1 /S checkpoint functions (Abraham, 2001), we particularly designed experiments to examine the effect of KU55933 treatment without the confounding factor of G 1 /S checkpoint inactivation. The NE2-hTERT and NP460-hTERT cells were treated with 10 mM KU55933 or dimethyl sulfoxide (DMSO) for 2.5 h, with the addition of colcemid 0.5 h after KU55933 or DMSO treatment to enable the collection of metaphases accumulated from G 2 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Multiple pathways are able to upregulate cyclin B1. One of the well-studied classical pathways is through mutation or inactivation of ATM (Abraham, 2001). Another classical pathway is through inactivation of p53, which can regulate G 2 checkpoint through inhibition of cyclin B1 (Innocente et al, 1999), and p53 pathway inactivation has been detected in most cancers (Hanahan and Weinberg, 2000).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Impact of G2 checkpoint defect on centromeric instability

et al. 2010

View full text Add to dashboard Cite

Centromeric instability is characterized by dynamic formation of centromeric breaks, deletions, isochromosomes and translocations, which are commonly observed in cancer. So far, however, the mechanisms of centromeric instability in cancer cells are still poorly understood. In this study, we tested the hypothesis that G 2 checkpoint defect promotes centromeric instability. Our observations from multiple approaches consistently support this hypothesis. We found that overexpression of cyclin B1, one of the pivotal genes driving G 2 to M phase transition, impaired G 2 checkpoint and promoted the formation of centromeric aberrations in telomerase-immortalized cell lines. Conversely, centromeric instability in cancer cells was ameliorated through reinforcement of G 2 checkpoint by cyclin B1 knockdown. Remarkably, treatment with KU55933 for only 2.5 h, which abrogated G 2 checkpoint, was sufficient to produce centromeric aberrations. Moreover, centromeric aberrations constituted the major form of structural abnormalities in G 2 checkpoint-defective ataxia telangiectasia cells. Statistical analysis showed that the frequencies of centromeric aberrations in G 2 checkpoint-defective cells were always significantly overrepresented compared with random assumption. As there are multiple pathways leading to G 2 checkpoint defect, our finding offers a broad explanation for the common occurrence of centromeric aberrations in cancer cells.

show abstract

ATM/miR‐34a‐5p axis regulates a p21‐dependent senescence‐apoptosis switch in non‐small cell lung cancer: a Boolean model of G1/S checkpoint regulation

2019

View full text Add to dashboard Cite

MicroRNA-34a-5p regulates the G1/S checkpoint in non-small cell lung cancer (NSCLC) cells. Forced expression of miR-34a-5p enhances p21 expression and promotes cellular senescence, whereas knockout of miR-34a-5p decreases senescence and increases apoptosis. This suggests that p21 is the main effector of a senescence-apoptosis switch in NSCLC cells; however, the molecular mechanisms controlling this switch are unclear. In this work, we propose a Boolean model of G1/S checkpoint regulation, contemplating the regulatory influences of p21 by miR-34a-5p. The predicted probabilities of our model are in excellent agreement with experimental data. Our model supports that p21 is the main effector of a senescence/apoptosis switch and that the disruption of the positive feedback involving ATM, miR-34a-5p, and the histone deacetylase HDAC1 abrogates senescence.

show abstract

Cell cycle checkpoint signaling through the ATM and ATR kinases

Cited by 1,833 publications

References 142 publications

Interplay between ATM and ATR in the regulation of common fragile site stability

Interplay between ATM and ATR in the regulation of common fragile site stability

Impact of G2 checkpoint defect on centromeric instability

ATM/miR‐34a‐5p axis regulates a p21‐dependent senescence‐apoptosis switch in non‐small cell lung cancer: a Boolean model of G1/S checkpoint regulation

Contact Info

Product

Resources

About