ATR Autophosphorylation as a Molecular Switch for Checkpoint Activation

Liu, Shizhou; Shiotani, Bunsyo; Lahiri, Mayurika; Maréchal, Alexandre; Tse, Alice; Leung, Charles Chung Yun; Glover, J. N. Mark; Yang, Xiaohong; Zou, Lee

doi:10.1016/j.molcel.2011.06.019

Cited by 226 publications

(238 citation statements)

References 61 publications

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“…v-Src suppressed Rad17 phosphorylation (Fig. 6C) (86) induced by thymidine (data not shown), indicating that replication stress is induced. Furthermore, we confirmed that v-Src suppresses Chk1 phosphorylation without affecting thymidine arrest.…”

Section: Discussionmentioning

confidence: 80%

Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Fukumoto

Morii

Miura

et al. 2014

Journal of Biological Chemistry

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Background: Once DNA repair is completed, the DNA damage checkpoint is terminated, and the cell cycle is resumed. Results: Src inhibition induced a delay in G 2 checkpoint recovery and persistent ATR-Chk1 activation. Conclusion: Src inhibits ATR signaling to promote recovery from G 2 checkpoint arrest. Significance: Src sends a termination signal between the completion of DNA repair and the initiation of checkpoint termination.

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Section: Discussionmentioning

confidence: 80%

Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Fukumoto

Morii

Miura

et al. 2014

Journal of Biological Chemistry

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“…8) and emphasize the role of posttranslational acetylation in the regulation of Sirt1 activity. Autocatalytic modifications of proteins are common and have been primarily described for kinases (30), acetyltransferases (31), and also for phosphatases (32) but not for deacetylases. An involvement of acetylation/deacetylation in the regulation of enzymatic activity of this class of proteins has mostly remained enigmatic, although acetylation of several protein deacetylases has been reported previously (33).…”

Section: Discussionmentioning

confidence: 99%

Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1

Fang

Ianni

Smolka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Sirtuins (Sirt1-Sirt7) are NAD + -dependent protein deacetylases/ ADP ribosyltransferases, which play decisive roles in chromatin silencing, cell cycle regulation, cellular differentiation, and metabolism. Different sirtuins control similar cellular processes, suggesting a coordinated mode of action but information about potential cross-regulatory interactions within the sirtuin family is still limited. Here, we demonstrate that Sirt1 requires autodeacetylation to efficiently deacetylate targets such as p53, H3K9, and H4K16. Sirt7 restricts Sirt1 activity by preventing Sirt1 autodeacetylation causing enhanced Sirt1 activity in Sirt7 −/− mice. Increased Sirt1 activity in Sirt7 −/− mice blocks PPARγ and adipocyte differentiation, thereby diminishing accumulation of white fat. Thus, reduction of Sirt1 activity restores adipogenesis in Sirt7 −/− adipocytes in vitro and in vivo. We disclosed a principle controlling Sirt1 activity and uncovered an unexpected complexity in the crosstalk between two different sirtuins. We propose that antagonistic interactions between Sirt1 and Sirt7 are pivotal in controlling the signaling network required for maintenance of adipose tissue.sirtuin | acetylation | adipogenesis T he seven sirtuins in mammals (Sirt1-Sirt7) are involved in the regulation of essential cellular processes. Sirtuins rapidly adjust the activity of chromatin, transcription factors, metabolic enzymes, and structural proteins to cellular needs by deacetylating a broad range of targets. The ability to sense metabolic alterations and various stressors enable sirtuins to adapt cellular homeostasis to varying conditions. It seems likely that this feature of sirtuins is crucial to prevent age-dependent pathologies and promote a healthy lifespan (1, 2).Sirt1 is the most widely studied mammalian sirtuin showing the highest homology to the founding member of the sirtuin family, the yeast silence information regulator, Sir2. Sirt1 deacetylates histones H3K9, H3K56, H4K16, and H1K26 as well as many nonhistone targets thereby contributing to the maintenance of metabolic homeostasis and genomic integrity (3, 4). Sirt1 was also identified as a critical component of lifespan extension in response to calorie restriction in several model organisms, although its exact contribution is still under debate (5). The functions of Sirt7 have attracted less attention compared with Sirt1.

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“…ATR has been shown to phosphorylate itself on Thr1989 in asynchronous populations of cells exposed to inducers of replication stress (43,44). To determine whether this residue becomes phosphorylated in non-replicating cells, I exposed both cycling and non-cycling cells to NA-AAF and then monitored Thr1989 phosphorylation by immunoblotting.…”

Section: Atr Autophosphorylation On Thr1989 In Noncycling Cellsmentioning

confidence: 99%

“…The checkpoint kinase CHK1 is a canonical substrate for ATR in replicating cells exposed to DNA damaging agents. However, in non-cycling cells, CHK1 protein is not present (19, 27, 28) and therefore no CHK1 phosphorylation is observed following exposure to NA-AAF (Figure 2A).ATR has been shown to phosphorylate itself on Thr1989 in asynchronous populations of cells exposed to inducers of replication stress (43,44). To determine whether this residue becomes phosphorylated in non-replicating cells, I exposed both cycling and non-cycling cells to NA-AAF and then monitored Thr1989 phosphorylation by immunoblotting.…”

mentioning

confidence: 99%

DNA damage-induced ATM- and Rad-3-related (ATR) kinase activation in non-replicating cells is regulated by the XPB subunit of transcription factor IIH (TFIIH)

Kemp

2017

Journal of Biological Chemistry

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The role of the DNA damage response protein kinase ataxia telangiectasia and Rad-3-related (ATR) in the cellular response to DNA damage during the replicative phase of the cell cycle has been extensively studied. However, little is known about ATR kinase function in cells that are not actively replicating DNA and which constitute most cells in the human body. Using small-molecule inhibitors of ATR kinase and overexpression of a kinase-inactive form of the enzyme, I show here that ATR promotes cell death in non-replicating/non-cycling cultured human cells exposed to N-acetoxy-2-acetylaminofluorene (NA-AAF), which generates bulky DNA adducts that block RNA polymerase movement. Immunoblot analyses of soluble protein extracts revealed that ATR and other cellular proteins containing SQ motifs become rapidly and robustly phosphorylated in non-cycling cells exposed to NA-AAF in a manner largely dependent on ATR kinase activity but independent of the essential nucleotide excision repair factor XPA. Although the topoisomerase I inhibitor camptothecin also activated ATR in noncycling cells, other transcription inhibitors that do not directly damage DNA failed to do so. Interestingly, genetic and pharmacological inhibition of the XPB subunit of transcription factor IIH (TFIIH) prevented the accumulation of the single-stranded DNA binding protein RPA on damaged chromatin and severely abrogated ATR signaling in response to NA-AAF and camptothecin. Together, these results reveal a previously unknown role for TFIIH in ATR kinase activation in non-replicating, noncycling cells.As one of the major DNA damage response signaling kinases in mammalian cells, the ATR 1 (ataxia telangiectasia and Rad3-related) kinase is primarily thought to respond to DNA polymerase stalling and uncoupling from DNA helicase activity as a result of template lesions or deoxyribonucleotide (dNTP) shortage (1-3). These replicative stress events are characterized by regions of single-stranded DNA (ssDNA) and a junction of ssDNA and dsDNA (5'-primertemplate junction), which together serve to recruit ATR and accessory proteins to ultimately activate ATR kinase signaling (2, 4). The functional outcomes of ATR activation in response to replication stress generally involve processes that ultimately promote cell survival, such as replication fork stabilization, cell cycle delay, inhibition of replication origin firing, DNA repair, and homologous recombination (2,5,6).These pro-survival functions of ATR in cells containing replication stress likely limit the therapeutic efficacy of anti-cancer drugs that damage DNA, and thus small molecule inhibitors of the ATR kinase are being developed as adjuvants in chemotherapy regimens (7-10). ATR kinase activation in non-cycling cellsPreliminary studies using mouse models of tumor progression have indeed suggested that ATR kinase inhibition can exacerbate the antiproliferative effects of radiation and cisplatin to more effectively slow tumor growth and shrink tumor volume (11,12).However, the majority of cells in ...

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ATR Autophosphorylation as a Molecular Switch for Checkpoint Activation

Cited by 226 publications

References 61 publications

Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1

DNA damage-induced ATM- and Rad-3-related (ATR) kinase activation in non-replicating cells is regulated by the XPB subunit of transcription factor IIH (TFIIH)

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