RGD Reference Report - Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death. - Rat Genome Database

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

Authors: Tian, B  Yang, Q  Mao, Z 
Citation: Tian B, etal., Nat Cell Biol. 2009 Feb;11(2):211-8. doi: 10.1038/ncb1829. Epub 2009 Jan 18.
RGD ID: 10053571
Pubmed: PMID:19151707   (View Abstract at PubMed)
PMCID: PMC2760486   (View Article at PubMed Central)
DOI: DOI:10.1038/ncb1829   (Journal Full-text)

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.

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
camptothecin increases activityISOAtm (Rattus norvegicus)10053571; 10053571camptothecin increases kinase activity in rat cerebellar granule neuronsRGD 
camptothecin increases activityEXP 10053571; 10053571; 10053571; 10053571camptothecin increases kinase activity in rat cerebellar granule neuronsRGD 
camptothecin increases activityISOCdk2 (Rattus norvegicus)10053571; 10053571camptothecin increases kinase activity in rat cerebellar granule neuronsRGD 
camptothecin increases activityISOCdk5 (Rattus norvegicus)10053571; 10053571camptothecin increases kinase activity in rat cerebellar granule neuronsRGD 
camptothecin increases activityISOCdk6 (Rattus norvegicus)10053571; 10053571camptothecin increases kinase activity in rat cerebellar granule neuronsRGD 
seliciclib increases expression ISOCdk2 (Rattus norvegicus)10053571; 10053571roscovitine (seliciclib) increases expression of mRNA inhibiting the reaction [camptothecin increases kinase activity] in rat cerebellar granule neuronsRGD 
seliciclib increases expression ISOCdk6 (Rattus norvegicus)10053571; 10053571roscovitine (seliciclib) increases expression of mRNA inhibiting the reaction [camptothecin increases kinase activity] in rat cerebellar granule neuronsRGD 
seliciclib increases expression EXP 10053571; 10053571roscovitine (seliciclib) increases expression of mRNA inhibiting the reaction [camptothecin increases kinase activity] in rat cerebellar granule neuronsRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
DNA damage response  IMP 10053571; 10053571; 10053571; 10053571 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Atm  (ATM serine/threonine kinase)
Cdk2  (cyclin dependent kinase 2)
Cdk5  (cyclin-dependent kinase 5)
Cdk6  (cyclin-dependent kinase 6)

Genes (Mus musculus)
Atm  (ataxia telangiectasia mutated)
Cdk2  (cyclin dependent kinase 2)
Cdk5  (cyclin dependent kinase 5)
Cdk6  (cyclin dependent kinase 6)

Genes (Homo sapiens)
ATM  (ATM serine/threonine kinase)
CDK2  (cyclin dependent kinase 2)
CDK5  (cyclin dependent kinase 5)
CDK6  (cyclin dependent kinase 6)


Additional Information