Research Paper Volume 4, Issue 12 pp 917—922
Ribonucleotide reductase and thymidylate synthase or exogenous deoxyribonucleosides reduce DNA damage and senescence caused by C-MYC depletion
- 1 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
- 2 Department of Dermatology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
- 3 Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
- 4 V.N. Orekhovich Institute of Biomedical Chemistry RAMS, 119121 Moscow, Russia
- 5 Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
Received: August 29, 2012 Accepted: December 10, 2012 Published: December 13, 2012
https://doi.org/10.18632/aging.100512How to Cite
Abstract
The down-regulation of dominant oncogenes, including C-MYC, in tumor cells often leads to the induction of senescence via mechanisms that are not completely identified. In the current study, we demonstrate that MYC-depleted melanoma cells undergo extensive DNA damage that is caused by the underexpression of thymidylate synthase (TS) and ribonucleotide reductase (RR) and subsequent depletion of deoxyribonucleoside triphosphate pools. Simultaneous genetic inhibition of TS and RR in melanoma cells induced DNA damage and senescence phenotypes very similar to the ones caused by MYC-depletion. Reciprocally, overexpression of TS and RR in melanoma cells or addition of deoxyribo-nucleosides to culture media substantially inhibited DNA damage and senescence-associated phenotypes caused by C-MYC depletion. Our data demonstrate the essential role of TS and RR in C-MYC-dependent suppression of senescence in melanoma cells.