DNA-dependent protein kinase is not required for accumulation of p53 or cell cycle arrest after DNA damage.
In response to DNA damage, cells transduce a signal that leads to accumulation and activation of p53 protein, transcriptional induction of several genes, including p21, gadd45, and gadd153, and cell cycle arrest. One hypothesis is that the signal is mediated by DNA-dependent protein kinase (DNA-PK), which consists of a catalytic subunit (DNA-PKcs) and a regulatory subunit (Ku). DNA-PK has several characteristics that support this hypothesis: Ku binds to DNA damaged by nicks or double-strand breaks, DNA-PKcs is activated when Ku binds to DNA, DNA-PK will phosphorylate p53 and other cell cycle regulatory proteins in vitro, and DNA-PKcs shares homology with ATM, which is mutated in ataxia telangiectasia and involved in signaling the p53 response to ionizing radiation. The hypothesis was tested by analyzing early passage fibroblasts from severe combined immunodeficient mice, which are deficient in DNA-PK. After exposure to ionizing radiation, UV radiation, or methyl methane-sulfonate, severe combined immunodeficient and wild-type cells were indistinguishable in their response. The accumulation of p53, induction of p21, gadd45, and gadd153, and arrest of the cell cycle in G1 and G2 occurred normally. Therefore, DNA-PK is not required for the p53 response or cell cycle arrest after DNA damage.
Rathmell
W K
WK
Department of Medicine, Stanford University School of Medicine, California 94305, USA.
Kaufmann
W K
WK
Hurt
J C
JC
Byrd
L L
LL
Chu
G
G
D000818:Animals; D000831:Animals, Newborn; D022762:CCAAT-Enhancer-Binding Proteins; D006224:Cricetinae; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000502:physiology*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D016193:G1 Phase / Q000235:genetics / Q000502:physiology*; D016195:G2 Phase / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000097642:GADD45 Proteins
D022762:CCAAT-Enhancer-Binding Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004247:DNA; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000097642:GADD45 Proteins; C493957:Cdkn1a protein, mouse; C497250:Ddit3 protein, mouse