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Title: 5′ End Nicotinamide Adenine Dinucleotide Cap in Human Cells Promotes RNA Decay through DXO-Mediated deNADding

Journal Article · · Cell

Eukaryotic mRNAs generally possess a 5′ end N7 methyl guanosine (m7G) cap that promotes their translation and stability. However, mammalian mRNAs can also carry a 5′ end nicotinamide adenine dinucleotide (NAD+) cap that, in contrast to the m7G cap, does not support translation but instead promotes mRNA decay. Here, the mammalian and fungal noncanonical DXO/Rai1 decapping enzymes efficiently remove NAD+ caps, and cocrystal structures of DXO/Rai1 with 3′-NADP+ illuminate the molecular mechanism for how the “deNADding” reaction produces NAD+ and 5′ phosphate RNA. Removal of DXO from cells increases NAD+-capped mRNA levels and enables detection of NAD+-capped intronic small nucleolar RNAs (snoRNAs), suggesting NAD+ caps can be added to 5′-processed termini. Our findings establish NAD+ as an alternative mammalian RNA cap and DXO as a deNADding enzyme modulating cellular levels of NAD+-capped RNAs. Collectively, these data reveal that mammalian RNAs can harbor a 5′ end modification distinct from the classical m7G cap that promotes rather than inhibits RNA decay.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health (NIH); NIH-ORIP HEI
Grant/Contract Number:
AC02-06CH11357; GM118059; GM118093; GM067005; P41 GM103403
OSTI ID:
1425226
Alternate ID(s):
OSTI ID: 1397486; OSTI ID: 1430324
Journal Information:
Cell, Journal Name: Cell Vol. 168 Journal Issue: 6; ISSN 0092-8674
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 130 works
Citation information provided by
Web of Science

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