Abstract
Timeless (Tim), a core circadian clock gene in Drosophila, is retained in mammals but has no apparent mammalian circadian clock function. Mammalian TIM is essential for ATR-dependent Chk1 activation and S-phase arrest. We report that TIM is likewise essential for ATM-dependent Chk2-mediated signaling of doxorubicin-induced DNA double strand breaks. TIM depletion attenuates doxorubicin-induced G(2)/M cell cycle arrest and sensitizes cancer cells to doxorubicin-induced cytotoxicity. TIM is, thereby, a potential novel anticancer drug target whose inhibition may enhance the therapeutic cytotoxicity of agents that activate DNA damage pathways as part of their mechanism.
MeSH terms
-
Ataxia Telangiectasia Mutated Proteins
-
Cell Cycle Proteins / metabolism*
-
Cell Division*
-
Cell Line, Tumor
-
Checkpoint Kinase 2
-
DNA Damage
-
DNA-Binding Proteins / metabolism*
-
Dose-Response Relationship, Drug
-
Doxorubicin / pharmacology
-
G2 Phase*
-
Gene Expression Regulation*
-
Histones / metabolism
-
Humans
-
Intracellular Signaling Peptides and Proteins / metabolism*
-
Phosphorylation
-
Protein Serine-Threonine Kinases / metabolism*
-
Time Factors
-
Tumor Suppressor Proteins / metabolism*
Substances
-
Cell Cycle Proteins
-
DNA-Binding Proteins
-
H2AX protein, human
-
Histones
-
Intracellular Signaling Peptides and Proteins
-
TIMELESS protein, human
-
Tumor Suppressor Proteins
-
Doxorubicin
-
Checkpoint Kinase 2
-
ATM protein, human
-
Ataxia Telangiectasia Mutated Proteins
-
CHEK2 protein, human
-
Protein Serine-Threonine Kinases