Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence

Abstract

Summary Oncogene-induced senescence is characterized by a stable cell growth arrest, thus providing a tumor suppression mechanism. However, the underlying mechanisms for this phenomenon remain unknown. Here we show that a decrease in deoxyribonucleotide triphosphates (dNTPs) levels underlies oncogene-induced stable senescence-associated cell growth arrest. The decrease in dNTP levels is caused by oncogene-induced repression of RRM2, the rate-limiting protein in dNTP synthesis. This precedes the senescence-associated cell cycle exit and coincides with the DNA damage response. Consistently, RRM2 downregulation is both necessary and sufficient for senescence. Strikingly, suppression of nucleotide metabolism by RRM2 repression is also necessary for maintenance of the stable senescence-associated cell growth arrest. Further, RRM2 repression correlates with senescence status in benign nevi and melanoma, and its knockdown drives senescence of melanoma cells. These data reveal the molecular basis whereby the stable growth arrest of oncogene-induced senescence is established and maintained through suppression of nucleotide metabolism.

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

“…RRM2 expression is upregulated in cancer and is associated with increased tumor aggressiveness, poor prognosis, and chemoresistance (11,(14)(15)(16). Here, we demonstrate that RRM2 expression is significantly upregulated in ER-negative as compared with ERpositive breast cancer cells, as is a 36-kDa variant of ER (ERa36; Fig.…”

“…Overexpression of the RRM2 subunit has been associated with malignant transformation and confers gemcitabine resistance (15). RRM2 functions in coordination with the S-phase checkpoint to regulate DNA damage, replication stress, and genomic instability, including mutagenesis (16,17). Because chronic incubation of tamoxifen induces DNA damage, cells may upregulate RRM2 in an attempt to repair the DNA damage and are thus able to survive as a resistant population.…”

Colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity

“…76), although it is unclear if this elevation is due to the fact that tumors have an increased proportion of S-phase cells that have high dNTP pools. More interestingly, pathways that regulate dNTP pools are often mutated in human cancers and cancer cell lines (77)(78)(79). These observations suggest a possibility that the mutator effects of replicative DNA polymerase variants could change along with dNTP levels as the tumors evolve.…”

NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation

“…Although DNA damage can arise through the direct interaction of oxidants with genomic DNA, it also can be generated by oxidation of DNA precursors in the nucleotide pool (23) or by an imbalance in the dNTP pools caused by inhibition of enzymes involved in nucleotide synthesis by ROS (24). Chronic depletion or imbalance in the nucleotide pool inflicted by radioinduced H 2 O 2 production may lead to replication stress with Catalase (250 U/mL) was added in the cell medium 2 d before cells were collected for Western blot analysis.…”