An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation

López-Contreras, Andrés J.; Gutierrez-Martinez, Paula; Specks, Julia; Rodrigo-Perez, Sara; Fernández-Capetillo, Óscar

doi:10.1083/jcb1965oia7

Cited by 25 publications

(46 citation statements)

References 27 publications

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“…Of note, the addition of an extra allele of Chk1 has even been found to promote Ras-or E1A-mediated transformation more efficiently in comparison to such transformation of wild-type littermates (Lopez-Contreras et al, 2012), suggesting that the ATR-Chk1 axis has a pro-malignant transformation role.…”

Section: Box 1 Relevance Of Atm and Atr Signaling In Cancermentioning

confidence: 99%

ATM and ATR signaling at a glance

Awasthi

Foiani

Kumar

2015

Journal of Cell Science

235

228

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There was an error published in J. Cell Sci. 128, 4255-4262.An incorrect citation and reference was given for the last sentence in Box 2. The correct citation and reference are: A recent review provides a detailed update on ATM and ATR inhibitors, and their potential as drug targets (Weber and Ryan, 2015).Weber, A.M. and Ryan, A.J. (2015). ATM and ATR as therapeutic targets in cancer. Pharmacol Ther. 149, 124-138.The authors apologise to the readers for any confusion that this error might have caused. Although the role of both ATM and ATR in DNA repair, cell cycle regulation and apoptosis have been well studied, both still remain in the focus of current research activities owing to their role in cancer. Recent advances in the field suggest that these proteins have an additional function in maintaining cellular homeostasis under both stressed and non-stressed conditions. In this Cell Science at a Glance article and the accompanying poster, we present an overview of recent advances in ATR and ATM research with emphasis on that into the modes of ATM and ATR activation, the different signaling pathways they participate in -including those that do not involve DNA damage -and highlight their relevance in cancer. 1285

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Section: Box 1 Relevance Of Atm and Atr Signaling In Cancermentioning

confidence: 99%

ATM and ATR signaling at a glance

Awasthi

Foiani

Kumar

2015

Journal of Cell Science

235

228

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“…44), checkpoint kinase Chk1 could be the most promising candidate to be targeted for prosenescence therapy, as Chk1 inhibitors are already in clinical trials (55). We recently demonstrated that inhibition of constitutive Chk1 activity in various cancer cell lines reduces CIP2A expression resulting in PP2A reactivation and potent inhibition of malignant cell growth (67), whereas increased Chk1 expression was shown to protect against oncogene-induced replicative stress and to promote transformation (68). Finally, as different PP2A complexes mediate senescence induction and regulate E2F1 (49), testing of efficacy of small-molecule activators of PP2A (17,47) as novel prosenescence therapeutic agents might be warranted.…”

Section: Senescence Induction In Cancer Cells With Compromised P53 Fumentioning

confidence: 99%

Molecular Pathways: Harnessing E2F1 Regulation for Prosenescence Therapy in p53-Defective Cancer Cells

Laine

Westermarck

2014

Clinical Cancer Research

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Induction of terminal proliferation arrest, senescence, is important for in vivo tumor-suppressive function of p53. Moreover, p53-mutant cells are highly resistant to senescence induction by either oncogenic signaling during cellular transformation or in response to different therapies. Senescence resistance in p53-mutant cells has been attributed mostly to inhibition of the checkpoint function of p53 in response to senescence-inducing stress signals. Here, we review very recent evidence that offers an alternative explanation for senescence resistance in p53-defective cancer cells: p21-mediated E2F1 expression. We discuss the potential relevance of these findings for senescence-inducing therapies and highlight cyclin-dependent kinases (CDK) and mechanisms downstream of retinoblastoma protein (RB) as prospective prosenescence therapeutic targets. In particular, we discuss recent findings indicating an important role for the E2F1-CIP2A feedback loop in causing senescence resistance in p53-compromised cancer cells. We further propose that targeting of the E2F1-CIP2A feedback loop could provide a prosenescence therapeutic approach that is effective in both p53-deficient and RB-deficient cancer cells, which together constitute the great majority of all cancer cells. Diagnostic evaluation of the described senescence resistance mechanisms in human tumors might also be informative for patient stratification for already existing therapies. Clin Cancer Res; 20(14); 3644-50. Ó2014 AACR.

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Section: Generation Of a Mouse Model With Increased Rrm2 Levelsmentioning

confidence: 99%

“…2C). This strategy, in contrast to classic transgenesis using plasmids harboring cDNA, has been proven successful for generating animals with increased activity of genes that are otherwise deleterious when aberrantly overexpressed, such as Chk1 or Tp53 (Garcia-Cao et al 2002;Lopez-Contreras et al 2012).Transgenic lines were identified by Southern blotting, and the integration site was subsequently mapped by inverse PCR. We selected one line (Rrm2 TG ) carrying several alleles integrated in tandem (Fig.…”

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IncreasedRrm2gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice

et al. 2015

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In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2 TG ) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity.Supplemental material is available for this article.Received December 5, 2014; revised version accepted March 2, 2015.Replication stress (RS) has emerged as a source of genome instability in human diseases, including cancer and premature aging (Lecona and Fernandez-Capetillo 2014;Zeman and Cimprich 2014). In brief, RS is defined by the accumulation of abnormal amounts of ssDNA at stalled replication forks that, due to its recombinogenic nature, can initiate genomic rearrangements. In mammals, RS is sensed and suppressed by a signaling cascade initiated by the ATR kinase, which, together with its target kinase, CHK1, suppresses RS through the phosphorylation of multiple targets (Cimprich and Cortez 2008;Lopez-Contreras and Fernandez-Capetillo 2010). ATR and CHK1 are essential for embryonic development in mice (Brown and Baltimore 2000;de Klein et al. 2000;Liu et al. 2000), which is due to the role of the RS response (RSR) in preventing replication-born chromosome breakage. Whether the RSR protects all forks or a subset of them during replication is unclear. On the one hand, proteomic studies of the human replisome in unchallenged conditions have failed to detect ATR or CHK1 in the vicinity of replication forks Sirbu et al. 2013), suggesting that their activity might be particularly necessary for only a subset of forks, such as damaged ones. Accordingly, chromosomal breaks that arise upon ATR inactivation locate preferentially at specific loci named common fragile sites (CFSs) (Casper et al. 2002) and early replicating fragile sites (ERFSs) (Barlow et al. 2013). Regardless of whether ATR works at all forks or only some of them, how it suppresses RS and why it is essential are still not fully understood.Ribonucleotide reductase (RNR) is a tetrameric enzyme composed of two catalytic (RRM1, Rnr1 in yeast) and two regulatory (RRM2, Rnr2 in yeast) subunits (Jordan and Reichard 1998). It reduces NDPs into dNDPs, which is a rate-limiting step for the production of dNTPs. In yeast, the lethality of mec1Δ strains can be bypassed by mutations that increase RNR activity. The first evidence of a connection between ATR and RNR came from the discovery of Crt1 (a transcriptional repressor of RNR subunits) as a suppressor of Mec1 lethality in Saccharomyces cerevisiae (Huang et al. 1998). Furthermore, overproduction of Rnr1 was shown to be sufficient ...

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An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation

Cited by 25 publications

References 27 publications

ATM and ATR signaling at a glance

ATM and ATR signaling at a glance

Molecular Pathways: Harnessing E2F1 Regulation for Prosenescence Therapy in p53-Defective Cancer Cells

IncreasedRrm2gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice

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