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.

An increase in Ap 4 A resulting from activation of synthesis, inhibition of degradation or both has been implicated in several intracellular processes. Genotoxic, thermal and other stresses lead to increased Ap 4 A [13] [14] [15] [16] [17] and so Ap 4 A has been implicated in the regulation of DNA replication after DNA damage and in promoting apoptosis [17] [18] [19] . Ap 4 A may also be raised in response to external ligands and act as an intracellular second messenger [20] [21] [22] . It also acts as an extracellular messenger through its interaction with a number of P2-type receptors [23] . Ap 4 A is also a ligand for a number of proteins including a multiprotein complex containing DNA polymerase-α [24, 25] , protein kinases [26] [27] [28] , uracil-DNA glycosylase [29] , protein chaperones [30] , the HINT1 tumor suppressor [31] , 5 0 -nucleotidase II [32] , CBS domain proteins [33, 34] and CFIm25 [35] , but in most cases the significance of this binding is not clear. Of particular interest, however, is the possibility that Ap 4 A may act as a transcriptional regulator. It has been suggested that an increased level of Ap 4 A induced in mast cells by external factors activates the expression of a subset of genes controlled by the MITF and USF2 transcription factors by binding to and displacing the inhibitory HINT1 protein from these factors [10, 31, 36] .