Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2

Xu, Ning; Hégarat, Nadia; Black, Elizabeth J.; Scott, Mary T.; Hochegger, Helfrid; Gillespie, David A.

doi:10.1083/jcb.201003004

Cited by 66 publications

(68 citation statements)

References 34 publications

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“…Recent studies have shown that activation of the ATRChk1 pathway in response to DSBs increases as cell progress through the cell cycle (Jazayeri et al, 2006;Walker et al, 2009;Xu et al, 2010). By analyzing ATRmediated Chk1 S345 phosphorylation in individual DT40 cells at defined points in the cell cycle, we find that the situation is more complex than simple restriction of DNA damage-induced ATR-Chk1 activation to the later S and G2 phases when Cdk activity is high (Jazayeri et al, 2006).…”

Section: Discussionmentioning

confidence: 85%

“…Chk1 activation in response to DNA damage is minimal in G1, maximal in S phase, and declines again and G2 Previously, we found that irradiation-induced Chk1 activation varies according to cell cycle position using elutriation (Walker et al, 2009;Xu et al, 2010), however, this approach did not allow comparison of levels of activation specifically in G1, S and G2/M phase. To refine this analysis, we examined the relationship between cell cycle position and Chk1 activation in individual cells.…”

Section: Resultsmentioning

confidence: 95%

“…One possibility is that Cdk phosphorylation may induce a conformational change in the Chk1 regulatory domain, thus exposing or 'priming' the adjacent S345 activation site for efficient modification by ATR (Walker et al, 2009). Interestingly, several lines of evidence suggest that proficiency for ATR activation is either attenuated or switched off immediately before and during mitosis (Shiromizu et al, 2006;Xu et al, 2010). This could perhaps provide an explanation for why Cdk phosphorylation appears to inhibit Chk1 function during the G2/M transition (Enomoto et al, 2009) and yet is required for optimal activation and checkpoint proficiency under conditions of damage.…”

Section: Discussionmentioning

confidence: 99%

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Cdk-mediated phosphorylation of Chk1 is required for efficient activation and full checkpoint proficiency in response to DNA damage

Libertini

Black

et al. 2011

Oncogene

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Here, we show that activation of the checkpoint effector kinase Chk1 in response to irradiation-induced DNA damage is minimal in G1, maximal during S-phase and diminishes as cells enter G2. In addition, formation of irradiation-induced replication protein A (RPA)-coated single-stranded DNA (RPA-ssDNA), a structure required for ATM and Rad3-related (ATR)-Chk1 activation, occurs in a broadly similar pattern. Cyclin-dependent kinase (Cdk) activity is thought to promote RPA-ssDNA formation by stimulating DNA strand resection at doublestrand breaks (DSBs), providing one possible mechanism of imposing cell cycle dependence on DNA damage signaling. However, it has recently been shown that Chk1 itself is also subject to Cdk-mediated phosphorylation at serines 286 and 301 (S286 and 301). We show that Chk1 S301 phosphorylation increases as cells progress through S and G2 and that both Cdk1 and Cdk2 are likely to contribute to this modification in vivo. We also find that substitution of S286 and S301 with non-phosphorylatable alanine residues strongly attenuates DNA damage-induced Chk1 activation and G2 checkpoint proficiency, but does not eliminate the underlying cell cycle dependence of Chk1 regulation. Taken together, these data indicate that Cdk activity regulates multiple steps in the DNA damage response pathway including full activation of Chk1 and checkpoint proficiency.

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Section: Discussionmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Cdk-mediated phosphorylation of Chk1 is required for efficient activation and full checkpoint proficiency in response to DNA damage

Libertini

Black

et al. 2011

Oncogene

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“…However, the in vitro analysis reveals that Akt/PKB phosphorylates Chk1 at several sites, among which Ser280 is only a minor phosphorylation site . In addition, Chk1-Ser280 mutants behaved like Chk1 wild type in the G2/M checkpoint (Tonic et al, 2010;Xu et al, 2010). Although Akt/PKB negatively regulates the G2/M checkpoint (Henry et al, 2001;Nimbalkar and Quelle, 2008;Shtivelman et al, 2002;Xu et al, 2010), there is a debate as to whether G2/M checkpoint is negatively regulated by Chk1-Ser280 phosphorylation.…”

Section: Chk1 Phosphorylation At Ser280mentioning

confidence: 96%

Novel Insights into Chk1 Regulation by Phosphorylation

Kasahara

Inagaki

2015

Cell Struct. Funct.

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ABSTRACT. Checkpoint kinase 1 (Chk1) is a conserved protein kinase central to the cell-cycle checkpoint during DNA damage response (DDR). Until recently, ATR, a protein kinase activated in response to DNA damage or stalled replication, has been considered as the sole regulator of Chk1. Recent progress, however, has led to the identification of additional protein kinases involved in Chk1 phosphorylation, affecting the subcellular localization and binding partners of Chk1. In fact, spatio-temporal regulation of Chk1 is of critical importance not only in the DDR but also in normal cell-cycle progression. In due course, many potent inhibitors targeted to Chk1 have been developed as anticancer agents and some of these inhibitors are currently in clinical trials. In this review, we summarize the current knowledge of Chk1 regulation by phosphorylation.

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“…For instance, AKT1 destabilizes p53 via the phosphorylation of Mdm2 [54]; AKT1 controls the basal expression of XRCC1 [55]; the activation of AKT1 leads to the sequestration of CHK1 to the cytoplasm [47][48][49], and AKT1 phosphorylates and prevents the activation of CHK1 by ATR/ATM [56]; finally, AKT1 reduces the abundance of γ-gH2AX foci [57,58] in asynchronous cells, and inhibits the activation of CHK1 and the repair of DSBs at the end of G2 [59].…”

Section: Introductionmentioning

confidence: 99%

AKT1/BRCA1 in the control of homologous recombination and genetic stability: the missing link between hereditary and sporadic breast cancers

2010

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AbstrAct:Endogenous replicative stress could be one trigger leading to tumor initiation: indeed, activation of the DNA damage response (DDR), considered the result of replicative stress, is observed in pre-cancerous cells; moreover, in hereditary breast cancers, almost all of the genes affected relate to the DDR. The most frequently mutated gene in hereditary breast cancers, BRCA1, is essential for homologous recombination (HR), a fundamental process for maintaining genome stability that permits the reactivation of blocked replication forks . Recent studies have established links between DDR and the oncogenic kinase AKT1, which is upregulated in about 50% of sporadic breast cancers. More specifically, the activation of AKT1 shows a deficient phenotype in BRCA1 and HR, revealing molecular similarities between hereditary and sporadic breast cancers. However, these results reveal a paradox regarding the physiological role of AKT1: in non-tumor cells, AKT1 promotes cellular proliferation, but consequently endangers genome integrity during replication if HR is inhibited. Since HR could itself lead to genetic instability, we propose that, under physiological conditions, moderate activation of AKT1 does not inhibit but prevents an excess of HR. The regulation of AKT1 would represent a fine transitory system for controlling HR and maintaining genomic integrity.The coordination of a complex network of metabolic pathways ensures continued maintenance, duplication, and transmission of the genome. These metabolic pathways control the DNA damage response pathway (DDR) and bring together replication, recombination, DNA repair, chromosome segregation, and cell cycle control. However, in some common tightly-regulated processes, such as meiosis and the generation of the immune repertory, this network must allow/favor genetic diversity. Therefore, very precise regulation is necessary to control the equilibrium between genetic stability and diversity, while avoiding genetic instability. A defect in any of the actors in these pathways could result in genetic instability and a predisposition to tumor formation.Certain types of cancers correspond to areas exposed to oncogenic agents (often genotoxic), such as UV radiation for skin cancer or tobacco for throat or lung cancer. However, we emphasize that many cancers develop without substantial exposure to exogenous carcinogens. Therefore, endogenous stresses must play crucial roles in the etiology of cancer. For example, mutating the BRCA1 or BRCA2 genes confers a hereditary predisposition to breast cancer in the absence of exposure to exogenous genotoxic agents. the replicAtion/recombinAtion interfAce, genetic instAbility, And cAncer.Among endogenous stresses, the spontaneous blocking of replication forks could constitute a risk for spontaneous tumor initiation. In fact, DNA replication forks are regularly blocked by a variety of endogenous stresses that can result from bulging regions in the DNA, regions of hybrid DNA/RNA, and from endogenous metabolism of the cell [1]. Furthermore, ...

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Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2

Abstract: Activated Akt suppresses checkpoint activation by cells in late G2: although they are able to detect DNA damage, the repair pathway is put on hold until mitosis is complete.

Cited by 66 publications

References 34 publications

Cdk-mediated phosphorylation of Chk1 is required for efficient activation and full checkpoint proficiency in response to DNA damage

Cdk-mediated phosphorylation of Chk1 is required for efficient activation and full checkpoint proficiency in response to DNA damage

Novel Insights into Chk1 Regulation by Phosphorylation

AKT1/BRCA1 in the control of homologous recombination and genetic stability: the missing link between hereditary and sporadic breast cancers

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