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.
Highlights
In normal cells a form of irreversible proliferation arrest, termed senescence, is induced in response to aberrant activation of oncogenes and can be considered an intrinsic mechanism for suppressing tumor progression [1,2,3]
We and others have demonstrated that acute depletion of C-MYC in melanoma cells resulted in proliferation arrest that strikingly resembled oncogeneinduced senescence in normal cells [6]
Like in normal cells, senescence phenotypes in MYCdepleted melanoma cells depended on constitutively active BRAF or NRAS oncoproteins [6], but not on p53 or p16INK4A status [13]
Summary
In normal cells a form of irreversible proliferation arrest, termed senescence, is induced in response to aberrant activation of oncogenes and can be considered an intrinsic mechanism for suppressing tumor progression [1,2,3]. We have demonstrated that depletion of CMYC 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 (SAβ-Gal), and changes in histone modifications [6]. We have identified three bona fide MYC target genes that were down-regulated shortly after shRNA-mediated depletion of C-MYC: thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2), and phosphoribosyl pyrophosphate www.impactaging.com
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.