Decapping Enzyme NUDT12 Partners with BLMH for Cytoplasmic Surveillance of NAD-Capped RNAs

RNA polymerase II transcripts receive a protective 5ʹ,5ʹ-triphosphate-linked 7-methylguanosine (m7G) cap, and its removal by decapping enzymes like DCP2 is critical for initiation of RNA decay. Alternative RNA caps can be acquired when transcription initiation uses metabolites like nicotinamide adenine dinucleotide (NAD), generating NAD-RNAs. Here, we identify human NUDT12 as a cytosolic NAD-RNA decapping enzyme. NUDT12 is active only as homodimers, with each monomer contributing to creation of the two functional catalytic pockets. We identify an ∼600-kDa dodecamer complex between bleomycin hydrolase (BLMH) and NUDT12, with BLMH being required for localization of NUDT12 to a few discrete cytoplasmic granules that are distinct from P-bodies. Both proteins downregulate gene expression when artificially tethered to a reporter RNA in vivo. Furthermore, loss of Nudt12 results in a significant upregulation of circadian clock transcripts in mouse liver. Overall, our study points to a physiological role for NUDT12 in the cytosolic surveillance of NAD-RNAs. [Display omitted] •Human NUDT12 is a decapping enzyme for NAD-capped RNAs•Homodimerization of NUDT12 creates two interdependent catalytic pockets•Interaction with BLMH facilitates localization of NUDT12 to cytoplasmic granules•Nudt12 knockout mice upregulate circadian clock transcripts Wu et al. identify NUDT12 as a decapping enzyme for NAD-capped RNAs and demonstrate a role for the enzyme in regulation of circadian clock transcripts in mice. They reveal the existence of a BLMH-NUDT12 complex that facilitates localization of NUDT12 to distinct cytoplasmic granules.