Mammalian TIMELESS Is Required for ATM-dependent CHK2 Activation and G2/M Checkpoint Control*
- From the ‡Medical Chronobiology Laboratory, Wm. Jennings Bryan Dorn Veterans Affairs Medical Center, and
- the Schools of §Medicine,
- ¶Public Health, and
- ‖Engineering and Computer Science, University of South Carolina, Columbia, South Carolina 29209
- 1 To whom correspondence should be addressed: Wm. Jennings Bryan Dorn Veterans Affairs Medical Center, 6439 Garners Ferry Rd., Columbia, SC 29209. Tel.: 803-695-6825; Fax: 803-695-6829. E-mail: williamhrushesky{at}gmail.com.
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 G2/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.
Footnotes
-
↵2 The abbreviations used are:
- DSB
- double strand break
- Dox
- doxorubicin
- siRNA
- small interfering RNA.
-
- Received August 10, 2009.
- Revision received November 12, 2009.
- © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
