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.

Nudix hydrolases regulate the levels of a wide variety of canonical and modified nucleotides and some non-nucleotide phosphorylated substrates as well as participating in essential processes such as mRNA decapping [1, 2] . One of the best studied is mammalian NUDT2. This enzyme has been isolated from many sources [3, 4] and its principal substrate is believed to be diadenosine 5 0 ,5 000 -P 1 ,P 4 -tetraphosphate (Ap 4 A). In animal cells, Ap 4 A can be synthesized by most aminoacyl-tRNA synthetases, DNA ligases, firefly luciferase and acyl-CoA synthetases while a further range of enzymes is able to do so in plants, fungi and bacteria [5] [6] [7] . Synthesis usually involves transfer of AMP from an acyl-AMP or enzyme-AMP reaction intermediate to an ATP acceptor. It can also be degraded by a number of enzymes in addition to NUDT2, including FHIT [8] , aprataxin [9] and non-specific phosphodiesterases [3] . However, NUDT2 is believed to be principally responsible for maintaining the low level of intracellular Ap 4 A [10] [11] [12] .