Our results suggest that after p53 loss, R1, R2, dCK, TK1 and dGK increase, and TK2 decreases. We speculate that genes that increased prioritize nuclear dNTP demands, and by meeting them, overproduce deoxypyrimidines with respect to mitochondrial demands. In contrast, we speculate that TK2 is more dedicated to meeting mitochondrial dNTP demands, so it compensates for what it sees as cytosolic dNTP concentrations that are too high by decreasing its level so that within mitochondria, dNTP supply matches dNTP demand. In this picture, relative to TK2, dGK has broader obligations to both nuclear and mitochondrial dNTP demands, consistent with dCK’s affinity for dG being much less than dGK’s affinity for dG [23
] and dCK thus being in need of help from dGK for purine dNTP supply control. That such compensations are incapable of overcoming complete p53R2 loss is evidenced by mitochondrial DNA depletion in muscles of children with p53R2 defects [22
]. However, as our findings are only at the mRNA level, they await confirmation at the protein level and thus remain highly speculative. Also, other enzymes of dNTP supply were explored (, , and , corresponding to , , and ) but they did not reveal a consistent pattern, e.g., TYMS was elevated in all of the datasets save our own. , , and did, however, confirm p53 losses, as MDM2 and CDKN1A, viewed as reporters of p53, did decrease with losses of p53.
Because pyrimidine and purine nucleoside analogue oncotherapies require cellular uptake by salvage pathways and are antagonized by de novo
pathway activity [24
], alterations in these pathways induced by p53 loss may be an important element in the therapeutic index of these drugs, particularly for the pyrimidine analogue decitabine that can induce cell cycle exit independent of p53 [5
A logical next step is to develop mathematical models of dNTP supply [25
] that incorporate our findings, and use the models for control system design [26
., to optimize nucleoside analogue cancer therapies [28
] using methods proposed for chronic myeloid leukemia [29
]. We believe that it is through such applications that systems biology will have its greatest impact on cancer therapy.