NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap(4)A) and Down-Regulates Immune Response and Cancer Promotion Genes

Marriott, Andrew S.; Vasieva, Olga; Fang, Yongxiang; Copeland, Nikki A.; McLennan, Alexander G.; Jones, Nigel J.

Despite being known since the 1960s, Ap 4 A has never commanded the attention that has been bestowed on other low-molecular-weight regulators such as cyclic nucleotides and inositol phosphates. Two competing schools of thought have arisen, one suggesting that Ap 4 A is a physiologically important regulator whose level is finely tuned by the NUDT2 Ap 4 A hydrolase, and the other that it is an unavoidable, non-functional by-product of several enzyme activities and that NUDT2 exists simply to eliminate it, lest it cause molecular mayhem by interfering with essential, adenine nucleotide-dependent metabolic and regulatory pathways [4] . The data presented here clearly demonstrate that increases in intracellular Ap 4 A by disruption of a single gene lead to significant changes to the transcriptional program. While some of the observed changes in gene expression may indeed be adventitious due to an unregulated and sustained high level of Ap 4 A, the specific down-regulation of gene sets involved in the interferon, inflammatory and innate immune responses and in cancer promotion support the view that Ap 4 A is indeed a biologically relevant regulator. Assuming that Ap 4 A has more than one intracellular target, it is likely that different gene sets will respond to different levels of Ap 4 A resulting from the regulation of NUDT2 activity, translation or transcription in vivo in response to different factors, and so not all the effects observed in NuKO cells will necessarily occur at the same time. Identification of these targets and the gene networks under their control is a priority for future work.