Phosphorylation of ATM by Cdk5 Mediates DNA Damage Signalling and Regulates Neuronal Death

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2009 Jan 20

PMID 19151707

Citations 90

Authors

Bo Tian

Qian Yang

Zixu Mao

Affiliations

Soon will be listed here.

Abstract

The phosphatidylinositol-3-kinase-like kinase ATM (ataxia-telangiectasia mutated) has a central role in coordinating DNA damage responses, including cell-cycle checkpoint control, DNA repair and apoptosis. Mutations of ATM cause a spectrum of defects ranging from neurodegeneration to cancer predisposition. However, the mechanism by which DNA damage activates ATM is poorly understood. Here we show that Cdk5 (cyclin-dependent kinase 5), activated by DNA damage, directly phosphorylates ATM at Ser 794 in post-mitotic neurons. Phosphorylation at Ser 794 precedes, and is required for, ATM autophosphorylation at Ser 1981, and activates ATM kinase activity. The Cdk5-ATM signal regulates phosphorylation and function of the ATM targets p53 and H2AX. Interruption of the Cdk5-ATM pathway attenuates DNA-damage-induced neuronal cell cycle re-entry and expression of the p53 targets PUMA and Bax, protecting neurons from death. Thus, activation of Cdk5 by DNA damage serves as a critical signal to initiate the ATM response and regulate ATM-dependent cellular processes.

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References

Herrup K, Neve R, Ackerman S, Copani A . Divide and die: cell cycle events as triggers of nerve cell death. J Neurosci. 2004; 24(42):9232-9. PMC: 6730083. DOI: 10.1523/JNEUROSCI.3347-04.2004. View

Hickson I, Zhao Y, Richardson C, Green S, Martin N, Orr A . Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 2004; 64(24):9152-9. DOI: 10.1158/0008-5472.CAN-04-2727. View

Falck J, Coates J, Jackson S . Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature. 2005; 434(7033):605-11. DOI: 10.1038/nature03442. View

Roos W, Kaina B . DNA damage-induced cell death by apoptosis. Trends Mol Med. 2006; 12(9):440-50. DOI: 10.1016/j.molmed.2006.07.007. View

Lee M, Kwon Y, Li M, Peng J, Friedlander R, Tsai L . Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature. 2000; 405(6784):360-4. DOI: 10.1038/35012636. View

McKinnon P . ATM and ataxia telangiectasia. EMBO Rep. 2004; 5(8):772-6. PMC: 1299121. DOI: 10.1038/sj.embor.7400210. View

Kruman I, Wersto R, Cardozo-Pelaez F, Smilenov L, Chan S, Chrest F . Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron. 2004; 41(4):549-61. DOI: 10.1016/s0896-6273(04)00017-0. View

Copani A, Uberti D, Sortino M, Bruno V, Nicoletti F, Memo M . Activation of cell-cycle-associated proteins in neuronal death: a mandatory or dispensable path?. Trends Neurosci. 2001; 24(1):25-31. DOI: 10.1016/s0166-2236(00)01663-5. View

El-Deiry W, Tokino T, Velculescu V, Levy D, Parsons R, Trent J . WAF1, a potential mediator of p53 tumor suppression. Cell. 1993; 75(4):817-25. DOI: 10.1016/0092-8674(93)90500-p. View

10.

Khanna K, Lavin M, Jackson S, MULHERN T . ATM, a central controller of cellular responses to DNA damage. Cell Death Differ. 2001; 8(11):1052-65. DOI: 10.1038/sj.cdd.4400874. View

11.

Tang X, Wang X, Gong X, Tong M, Park D, Xia Z . Cyclin-dependent kinase 5 mediates neurotoxin-induced degradation of the transcription factor myocyte enhancer factor 2. J Neurosci. 2005; 25(19):4823-34. PMC: 6724765. DOI: 10.1523/JNEUROSCI.1331-05.2005. View

12.

Jamsa A, Hasslund K, Cowburn R, Backstrom A, Vasange M . The retinoic acid and brain-derived neurotrophic factor differentiated SH-SY5Y cell line as a model for Alzheimer's disease-like tau phosphorylation. Biochem Biophys Res Commun. 2004; 319(3):993-1000. DOI: 10.1016/j.bbrc.2004.05.075. View

13.

Xiao H, Mao Y, Desai S, Zhou N, Ting C, Hwang J . The topoisomerase IIbeta circular clamp arrests transcription and signals a 26S proteasome pathway. Proc Natl Acad Sci U S A. 2003; 100(6):3239-44. PMC: 152276. DOI: 10.1073/pnas.0736401100. View

14.

Park D, Morris E, Padmanabhan J, Shelanski M, Geller H, Greene L . Cyclin-dependent kinases participate in death of neurons evoked by DNA-damaging agents. J Cell Biol. 1998; 143(2):457-67. PMC: 2132832. DOI: 10.1083/jcb.143.2.457. View

15.

Gong X, Tang X, Wiedmann M, Wang X, Peng J, Zheng D . Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron. 2003; 38(1):33-46. DOI: 10.1016/s0896-6273(03)00191-0. View

16.

Pommier Y . Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006; 6(10):789-802. DOI: 10.1038/nrc1977. View

17.

Dupre A, Boyer-Chatenet L, Gautier J . Two-step activation of ATM by DNA and the Mre11-Rad50-Nbs1 complex. Nat Struct Mol Biol. 2006; 13(5):451-7. DOI: 10.1038/nsmb1090. View

18.

Sun Y, Jiang X, Chen S, Fernandes N, Price B . A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proc Natl Acad Sci U S A. 2005; 102(37):13182-7. PMC: 1197271. DOI: 10.1073/pnas.0504211102. View

19.

Gupta A, Sharma G, Young C, Agarwal M, Smith E, Paull T . Involvement of human MOF in ATM function. Mol Cell Biol. 2005; 25(12):5292-305. PMC: 1140595. DOI: 10.1128/MCB.25.12.5292-5305.2005. View

20.

Lee Y, Chong M, McKinnon P . Ataxia telangiectasia mutated-dependent apoptosis after genotoxic stress in the developing nervous system is determined by cellular differentiation status. J Neurosci. 2001; 21(17):6687-93. PMC: 6763074. View