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.

Chromatin remodeling. PARP1 and PARP2 are known to be intimately involved in chromatin (de)condensation and epigenetic marking through ADP-ribosylation of histones and chromatin remodeling enzymes and via interaction with numerous transcription factors, and this has profound effects on gene expression [145] . Ap 4 A can effectively compete with histones as an ADP-ribose acceptor resulting in the synthesis of ADPR-Ap 4 A species [17, 146, 147] and so an elevated level of Ap 4 A could conceivably regulate, or just interfere with, these processes leading to changes in gene regulation. However, the lack of effect on the expression of the selected gene set studied by qRT-PCR after inhibition of PARP1 and PARP2 would argue against a major role for PARPs. Nevertheless, the expression of a large number of histone gene variants is affected by NUDT2 disruption, the majority being down-regulated, while changes in the expression of several lysine-specific demethylases (KDMs), histone deactylases (HDACs) and DNA (cytosine-5)-methyltransferases (DNMTs), several of which are also ADP-ribosylation targets, is also evident (S3 Table) . Hence, Ap 4 A-mediated chromatin remodelling by some unknown mechanism could still be considered as a potential source of differential gene expression.