dNTP Supply Gene Expression Patterns after P53 Loss

Abstract

Loss of the transcription factor p53 implies mRNA losses of target genes such as the p53R2 subunit of human ribonucleotide reductase (RNR). We hypothesized that other genes in the dNTP supply system would compensate for such p53R2 losses and looked for this in our own data and in data of the Gene Expression Omnibus (GEO). We found that the de novo dNTP supply system compensates for p53R2 losses with increases in RNR subunit R1, R2, or both. We also found compensatory increases in cytosolic deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) and in mitochondrial deoxyguanosine kinase (dGK), all of the salvage dNTP supply system; in contrast, the remaining mitochondrial salvage enzyme thymidine kinase 2 (TK2) decreased with p53 loss. Thus, TK2 may be more dedicated to meeting mitochondrial dNTP demands than dGK which may be more obligated to assist cytosolic dNTP supply in meeting nuclear DNA dNTP demands.

Gemcitabine Resistance in Pancreatic Ductal Carcinoma Cell Lines Stems from Reprogramming of Energy Metabolism

“…In contrast, dCK downregulates antioxidant-associated genes via the NF-E2-related factor (NRF2)/antioxidant responsive element axis and inhibits ROS production [ 53 ]. Although dCK is a nucleoside kinase present in the cytoplasm that maintains the dNTP pool, it plays a role in supplying mitochondria with substrates for the biosynthesis of mtDNA [ 54 , 55 ]. Our data suggest that the downregulation of dCK might be associated with the impairment of mitochondrial function.…”

Bcl2 Induces DNA Replication Stress by Inhibiting Ribonucleotide Reductase

“…Endogenous Bcl2-induced reduction of RNR activity may slow down but not totally block DNA replication. A compensatory mechanism may also exist by regulating cytosolic deoxycytidine kinase or thymidine kinase 1 to ensure a basic rate of DNA replication in cells expressing endogenous Bcl2, as described (41). It is known that both hRRM1 and hRRM2 are localized in the cytoplasm (42).…”