Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death

Tian, Bo; Yang, Qian; Mao, Zixu

doi:10.1038/ncb1829

Cited by 170 publications

(153 citation statements)

References 37 publications

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“…To further test the enhancement of Cdk5 kinase activity by S-nitrosylation, we monitored phosphorylation of a second Cdk5 substrate, ATM, representing a pathway involved in neuronal cell death signaling (6,24). Similar results were obtained with ATM to those with histone H1; Cdk5 kinase activity increased after S-nitrosylation (Fig.…”

Section: No Enhances Cdk5supporting

confidence: 57%

“…In contrast, in the present study we demonstrate that under pathophysiologically relevant conditions, S-nitrosylation of Cdk5 stimulates enzymatic activity via reaction of NO at cysteine residues 83 and 157. This nitrosylation reaction leads to increased phosphorylation of substrates, including the proapoptotic serine/threonine-specific protein kinase, ataxia telangiectasia mutated (ATM) (6,24). Furthermore, we demonstrate that S-nitrosylation of Cdk5 occurs in human brains with AD and contributes to Aβ-and N-methyl-D-aspartate (NMDA)-induced dendritic spine loss.…”

mentioning

confidence: 93%

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S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

Nakamura

Cao

et al. 2011

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

169

182

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The activity of Cdk5 and its regulatory subunit p35 is thought to be important in both normal brain function and neurodegenerative disease pathogenesis. Increased Cdk5 activity, via proteolytic cleavage of p35 to a p25 fragment by the calcium-activated protease calpain or by phosphorylation at Cdk5(Tyr15), can contribute to neurotoxicity. Nonetheless, our knowledge of regulation of Cdk5 activity in disease states is still emerging. Here we demonstrate that Cdk5 is activated by S-nitrosylation or reaction of nitric oxide (NO)-related species with the thiol groups of cysteine residues 83 and 157, to form SNO-Cdk5. We then show that S-nitrosylation of Cdk5 contributes to amyloid-β (Aβ) peptide-induced dendritic spine loss. Furthermore, we observed significant levels of SNO-Cdk5 in postmortem Alzheimer's disease (AD) but not in normal human brains. These findings suggest that S-nitrosylation of Cdk5 is an aberrant regulatory mechanism of enzyme activity that may contribute to the pathogenesis of AD.C dk5 is a cyclin-dependent kinase that is activated by proteins p35, p25, and p39 (1-3). As a predominantly neuronalspecific kinase, Cdk5 lacks a role in cell-cycle control but has been implicated in an array of neuronal functions, including cell survival, axon guidance, neuronal migration, and regulation of synaptic spine density (4-6). Dysregulation of Cdk5 activity may play a role in the pathogenesis of stroke and several neurodegenerative disorders, including Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease (7-11). Cdk5 is also hyperactivated in response to oxidative stress, mitochondrial dysfunction, excitotoxicity, amyloid-β (Aβ) exposure, calcium overload, and neuroinflammation, thus contributing to neuronal damage. These neurotoxic stimuli activate calpain, which cleaves the Cdk5 activator p35 (or p39) into p25 (or p29); p25 accumulation thus contributes to Cdk5 activation (12-16). These changes trigger various events associated with neurodegeneration. Although increased Cdk5 activity has been observed in AD brains compared with nondemented control brains, the mechanism remains contentious (17).Similarly, nitric oxide (NO) and related species contribute to a number of neurodegenerative diseases. The major source of NO in neurons is neuronal nitric oxide synthase (NOS1). Excitotoxic stress increases intracellular Ca 2+ , which in turn activates NOS1, thus generating NO. In general, NO can stimulate soluble guanylate cyclase to form cGMP or can S-nitrosylate critical cysteine residues to regulate the activity of multiple target proteins, in some sense akin to phosphorylation. Indeed, S-nitrosylation may explain many cGMP-independent mechanisms of NO action in neurodegenerative diseases (18). Our group has demonstrated that NO contributes to neurodegenerative disorders by redox reaction consisting of S-nitrosylation; in some cases this reaction is followed by further oxidation. Proteins affected in this manner include the gelatinase enzyme matrix metalloprotineas...

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Section: No Enhances Cdk5supporting

confidence: 57%

mentioning

confidence: 93%

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

Nakamura

Cao

et al. 2011

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

169

182

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“…The finding that the up-regulation of miR-421 can alter the cellular radiosensitivity suggests that treatment of proliferating cancer cells with miR-421-inducing agents might sensitize them for radiotherapy. Conversely the finding that exposure of neuroblastoma cells to AMO-ATM increases ATM expression implies that AMO-ATM holds therapeutical potential for N-Myc-amplified neuroblastomas, perhaps by enhancing ATM-dependent apoptosis in response to DNA damage (34,35) or driving nondividing differentiated neuronal cells to reenter S-phase (36). Lastly, the suppression of ATM by miR-421 introduces two possible pathogenetic mechanisms for A-T: A mutation in the ATM 3′UTR might enhance the binding of miR-421, or a mutation of miR-421 might result in miR-421 overexpression, both leading to the down-regulation of ATM expression.…”

Section: Discussionmentioning

confidence: 99%

ATM is down-regulated by N-Myc–regulated microRNA-421

Nagabayashi

et al. 2010

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

236

176

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Ataxia-telangiectasia mutated (ATM) is a high molecular weight protein serine/threonine kinase that plays a central role in the maintenance of genomic integrity by activating cell cycle checkpoints and promoting repair of DNA double-strand breaks. Little is known about the regulatory mechanisms for ATM expression itself. MicroRNAs are naturally existing regulators that modulate gene expression in a sequence-specific manner. Here, we show that a human microRNA, miR-421, suppresses ATM expression by targeting the 3′-untranslated region (3′UTR) of ATM transcripts. Ectopic expression of miR-421 resulted in S-phase cell cycle checkpoint changes and an increased sensitivity to ionizing radiation, creating a cellular phenotype similar to that of cells derived from ataxiatelangiectasia (A-T) patients. Blocking the interaction between miR-421 and ATM 3′UTR with an antisense morpholino oligonucleotide rescued the defective phenotype caused by miR-421 overexpression, indicating that ATM mediates the effect of miR-421 on cell cycle checkpoint and radiosensitivity. Overexpression of the N-Myc transcription factor, an oncogene frequently amplified in neuroblastoma, induced miR-421 expression, which, in turn, downregulated ATM expression, establishing a linear signaling pathway that may contribute to N-Myc-induced tumorigenesis in neuroblastoma. Taken together, our findings implicate a previously undescribed regulatory mechanism for ATM expression and ATMdependent DNA damage response and provide several potential targets for treating neuroblastoma and perhaps A-T.neuroblastoma | S-phase checkpoint | radiosensitivity | DNA repair

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“…Moreover, c-Abl and Atr were found to form a complex when co-expressed in COS7 cells, which was also enhanced in the presence of Dox (Figure 5d). Physical interaction between c-Abl and Atm/Atr may facilitate activation of Atm/Atr, as TopBP1 does to Atr, 11 or c-Abl might phosphorylate Atm/Atr and lead to its activation, as CDK5 does to Atm, 12 or both. Figure 4e shows that c-Abl kinase activity is required for Atr activation.…”

Section: Dox (Hrs)mentioning

confidence: 99%

A positive role for c-Abl in Atm and Atr activation in DNA damage response

et al. 2010

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DNA damage triggers Atm-and/or Atr-dependent signaling pathways to control cell cycle progression, apoptosis, and DNA repair. However, how Atm and Atr are activated is not fully understood. One of the downstream targets of Atm is non-receptor tyrosine kinase c-Abl, which is phosphorylated and activated by Atm. The current view is that c-Abl relays pro-apoptotic signals from Atm to p73 and p53. Here we show that c-Abl deficiency resulted in a broad spectrum of defects in cell response to genotoxic stress, including activation of Chk1 and Chk2, activation of p53, nuclear foci formation, apoptosis, and DNA repair, suggesting that c-Abl might also act upstream of the DNA damage-activated signaling cascades in addition to its role in p73 and p53 regulation. Indeed, we found that c-Abl is required for proper activation of both Atm and Atr. c-Abl is bound to the chromatin and shows enhanced interaction with Atm and Atr in response to DNA damage. c-Abl can phosphorylate Atr on Y291 and Y310 and this phosphorylation appears to have a positive role in Atr activation under genotoxic stress. These findings suggest that Atm-mediated c-Abl activation in cell response to double-stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events. Cell Death and Differentiation (2011) 18, 5-15; doi:10.1038/cdd.2010; published online 27 August 2010 DNA damage can be caused by exogenous or endogenous factors such as ionizing radiation (IR), chemotherapeutic drugs, and stalled replication forks. 1 It is believed that various DNA lesions are eventually converted to double-stranded breaks (DSBs) and/or single-stranded DNA (ssDNA or SSBs), where sensors, mediators, transducers, and effectors assemble to form nuclear foci, which function as centers of signal propagation. At the core of the signaling network are PI-3 kinase-like kinases (PIKKs), including Atm, Atr and DNA-PKcs. 2 Atm is mainly activated by DSBs, whereas Atr responds to various DNA lesions. 3 Atm and Atr are recruited to the nuclear foci by the MRN (Mre11-Rad50-NBS) complex and ATRIP, respectively, 4,5 where they phosphorylate proteins such as p53, Chk1, Chk2, and H2AX, to activate cell cycle checkpoints and/or induce apoptosis. 6 Phosphorylation of Chk1 and Chk2 by Atr and Atm is facilitated by a group of nuclear foci proteins called mediators, for example, Brca1, TopBP1, and 53BP1. Furthermore, the nuclear foci also function as repair centers. 7 DSB repair is believed to involve an Atm to Atr switch. 8,9 Atm is first recruited to DSBs and ssDNA is later generated by resection of the DNA ends, where Atr can be assembled and activated. Thus, there exists a complex functional interaction between these two PIKKs. 10 Although several proteins have been reported to activate Atm or Atr, 11,12 the initial activation of Atm/Atr and the regulation of their activities in the process of DNA repair are poorly understood. 13,14 The c-Abl proto-oncogene encodes a non-receptor tyrosine kinase that is essential for perinatal survival in ...

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Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death

Cited by 170 publications

References 37 publications

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

ATM is down-regulated by N-Myc–regulated microRNA-421

A positive role for c-Abl in Atm and Atr activation in DNA damage response

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