Research Article: Ribonucleotide reductase and thymidylate synthase or exogenous deoxyribonucleosides reduce DNA damage and senescence caused by C-MYC depletion

Date Published: December 13, 2012

Publisher: Impact Journals LLC

Author(s): Sudha Mannava, Kalyana C. Moparthy, Linda J. Wheeler, Katerina I. Leonova, Joseph A. Wawrzyniak, Anna Bianchi-Smiraglia, Albert E. Berman, Sheryl Flanagan, Donna S. Shewach, Nathalie C. Zeitouni, Andrei V. Gudkov, Christopher K. Mathews, Mikhail A. Nikiforov.

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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.

Partial Text

In normal cells a form of irreversible proliferation arrest, termed senescence, is induced in response to aberrant activation of oncogenes and therefore can be considered an intrinsic mechanism for suppressing tumor progression [1-3]. In some types of tumor cells, a similar form of proliferation arrest can be caused by tumor suppressors or DNA damaging agents [4, 5]. Recently, we have demonstrated that depletion of C-MYC in human melanoma cells led to the induction of senescence-associated phenotypes that were very similar to that of normal melanocytes undergoing oncogene-induced senescence (OIS) [6]. These phenotypes included permanent growth arrest, elevated activity of senescence-associated β-galactosidase (SA-β-Gal), and changes in histone modifications [6]. Moreover, like in normal melanocytes, senescence phenotypes in MYC-depleted melanoma cells depended on constitutively active BRAF or NRAS oncoproteins and did not depend on the status of p53 or p16INK4A[6].

Recently, we and others have demonstrated that acute depletion of C-MYC in melanoma cells resulted in proliferation arrest that strikingly resembled oncogene-induced senescence in normal cells [6]. Moreover, like in normal cells, senescence phenotypes in MYC-depleted melanoma cells depended on constitutively active BRAF or NRAS oncoproteins [6], but not on p53 or p16INK4A status [13]. And although a crosstalk between Cdk2 and C-MYC was implicated in C-MYC induction and maintenance of senescence [14], C-MYC target genes responsible for continuous suppression of senescence in melanoma cells were not identified [6, 10]. Our present data demonstrate that at least one of the major causes of senescence in MYC-depleted melanoma cells is the down-regulation of TS- and RR-dependent dNTP pools.

 

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