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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
10
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pubmed:dateCreated |
2010-11-15
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pubmed:abstractText |
Intrigued by the dynamics of the seemingly contradictory yet integrated cellular responses to the requisites of preserving telomere integrity while also efficiently repairing damaged DNA, we investigated roles of the telomere associated poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) tankyrase 1 in both telomere function and the DNA damage response following exposure to ionizing radiation. Tankyrase 1 siRNA knockdown in human cells significantly elevated recombination specifically within telomeres, a phenotype with the potential of accelerating cellular senescence. Additionally, depletion of tankyrase 1 resulted in concomitant and rapid reduction of the nonhomologous end-joining protein DNA-PKcs, while Ku86 and ATM protein levels remained unchanged; DNA-PKcs mRNA levels were also unaffected. We found that the requirement of tankyrase 1 for DNA-PKcs protein stability reflects the necessity of its PARP enzymatic activity. We also demonstrated that depletion of tankyrase 1 resulted in proteasome-mediated DNA-PKcs degradation, explaining the associated defective damage response observed; i.e., increased sensitivity to ionizing radiation-induced cell killing, mutagenesis, chromosome aberration and telomere fusion. We provide the first evidence for regulation of DNA-PKcs by tankyrase 1 PARP activity and taken together, identify roles of tankyrase 1 with implications not only for DNA repair and telomere biology, but also for cancer and aging.
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/2-(morpholin-4-yl)benzo(h)chromen-4-...,
http://linkedlifedata.com/resource/pubmed/chemical/3-aminobenzamide,
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Diphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/Benzamides,
http://linkedlifedata.com/resource/pubmed/chemical/Chromones,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Activated Protein Kinase,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Glycoside Hydrolases,
http://linkedlifedata.com/resource/pubmed/chemical/Heterocyclic Compounds, 3-Ring,
http://linkedlifedata.com/resource/pubmed/chemical/Ku autoantigen,
http://linkedlifedata.com/resource/pubmed/chemical/Morpholines,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/PRKDC protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Poly(ADP-ribose) Polymerases,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrrolidines,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/TNKS protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Tankyrases,
http://linkedlifedata.com/resource/pubmed/chemical/XAV939,
http://linkedlifedata.com/resource/pubmed/chemical/adenosine diphosphate...,
http://linkedlifedata.com/resource/pubmed/chemical/poly ADP-ribose glycohydrolase
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1945-4589
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
2
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
691-708
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pubmed:meshHeading |
pubmed-meshheading:21037379-Adenosine Diphosphate,
pubmed-meshheading:21037379-Antigens, Nuclear,
pubmed-meshheading:21037379-Benzamides,
pubmed-meshheading:21037379-Biocatalysis,
pubmed-meshheading:21037379-Cell Death,
pubmed-meshheading:21037379-Cell Line, Transformed,
pubmed-meshheading:21037379-Cell Line, Tumor,
pubmed-meshheading:21037379-Chromones,
pubmed-meshheading:21037379-Chromosomal Instability,
pubmed-meshheading:21037379-Chromosome Aberrations,
pubmed-meshheading:21037379-DNA Repair,
pubmed-meshheading:21037379-DNA-Activated Protein Kinase,
pubmed-meshheading:21037379-DNA-Binding Proteins,
pubmed-meshheading:21037379-Electrophoresis, Polyacrylamide Gel,
pubmed-meshheading:21037379-Enzyme Inhibitors,
pubmed-meshheading:21037379-Fibroblasts,
pubmed-meshheading:21037379-Gene Expression,
pubmed-meshheading:21037379-Glycoside Hydrolases,
pubmed-meshheading:21037379-Heterocyclic Compounds, 3-Ring,
pubmed-meshheading:21037379-Humans,
pubmed-meshheading:21037379-Models, Biological,
pubmed-meshheading:21037379-Morpholines,
pubmed-meshheading:21037379-Mutation,
pubmed-meshheading:21037379-Nuclear Proteins,
pubmed-meshheading:21037379-Poly(ADP-ribose) Polymerases,
pubmed-meshheading:21037379-Proteasome Endopeptidase Complex,
pubmed-meshheading:21037379-Protein Processing, Post-Translational,
pubmed-meshheading:21037379-Pyrrolidines,
pubmed-meshheading:21037379-RNA, Small Interfering,
pubmed-meshheading:21037379-Sister Chromatid Exchange,
pubmed-meshheading:21037379-Tankyrases,
pubmed-meshheading:21037379-Telomere
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pubmed:year |
2010
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pubmed:articleTitle |
Regulatory roles of tankyrase 1 at telomeres and in DNA repair: suppression of T-SCE and stabilization of DNA-PKcs.
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pubmed:affiliation |
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, 80523-1618, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.
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