Ribonucleotide reductase and thymidylate synthase or exogenous deoxyribonucleosides reduce DNA damage and senescence...

Area of Science:

• Oncology
• Molecular Biology
• Cellular Senescence

Background:

• Oncogene down-regulation, such as C-MYC, can trigger senescence in tumor cells through incompletely understood pathways.
• Melanoma progression is linked to C-MYC activity and its role in cell cycle regulation and senescence evasion.

Purpose of the Study:

• To elucidate the molecular mechanisms by which C-MYC depletion induces DNA damage and senescence in melanoma cells.
• To investigate the role of thymidylate synthase (TS) and ribonucleotide reductase (RR) in C-MYC-mediated senescence suppression.

Main Methods:

• Genetic depletion of C-MYC in melanoma cell lines.
• Assessing DNA damage markers and senescence phenotypes.
• Modulating the expression of thymidylate synthase (TS) and ribonucleotide reductase (RR).
• Supplementing culture media with deoxyribonucleosides.

Main Results:

• C-MYC depletion in melanoma cells led to significant DNA damage and senescence.
• This damage was attributed to the underexpression of TS and RR, causing depletion of deoxyribonucleoside triphosphate pools.
• Genetic inhibition of TS and RR mimicked the DNA damage and senescence induced by C-MYC depletion.
• Overexpression of TS and RR, or addition of deoxyribonucleosides, protected against C-MYC depletion-induced DNA damage and senescence.

Conclusions:

• Thymidylate synthase (TS) and ribonucleotide reductase (RR) are essential for C-MYC's role in suppressing senescence in melanoma.
• The findings reveal a novel mechanism linking C-MYC, nucleotide metabolism, and senescence induction in cancer.