Effect of circadian clock mutations on DNA damage response in mammalian cells.
The circadian clock is a global regulatory mechanism that confers daily rhythmicity on many biochemical and physiological functions, including DNA excision repair in mammalian organisms. Here, we investigated the effect of the circadian clock on the major DNA damage response pathways by using mouse cell lines mutated in genes encoding proteins in the positive (Bmal1, CLOCK) or negative (Cry 1/2, Per 1/2) arms of the transcription-translation feedback loop that generates the circadian clock. We find that cells mutated in these genes are indistinguishable from wild-type in their response to UV, ionizing radiation and mitomycin C. We conclude that either the majority of DNA damage response reactions are not controlled by the circadian clock or that, even if such a control exists at the organism level, it is supplanted by homeostatic control mechanisms at the cellular level in tissue culture. We suggest that caution must be exercised in extrapolating from experiments in tissue culture to whole animals with respect to the effect of the circadian clock on cellular response to DNA damaging agents.
Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Shobhan
S
Gaddameedhi
Joyce T
JT
Reardon
Rui
R
Ye
Nuri
N
Ozturk
Aziz
A
Sancar
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D064447:Checkpoint Kinase 2; D057906:Circadian Clocks / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D025461:Feedback, Physiological / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008322:Mammals / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011839:Radiation, Ionizing; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014466:Ultraviolet Rays
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D016685:Mitomycin; D056926:CLOCK Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases