NAT10 and cytidine acetylation in mRNA: intersecting paths in development and disease

Abstract

N4-acetylcytidine (ac4C) is an RNA modification that is catalyzed by the enzyme NAT10. Constitutively found in tRNA and rRNA, ac4C displays a dynamic presence in mRNA that is shaped by developmental and induced shifts in NAT10 levels. However, deciphering ac4C functions in mRNA has been hampered by its context-dependent influences in translation and the complexity of isolating effects on specific mRNAs from other NAT10 activities. Recent advances have begun to overcome these obstacles by leveraging natural variations in mRNA acetylation in cancer, developmental transitions, and immune responses. Here, we synthesize the current literature with a focus on nuances that may fuel the perception of cellular discrepancies toward the development of a cohesive model of ac4C function in mRNA.

Figure 1.. ac4C RNA substrates and functions in human RNA.

ac4C is found within and stabilizes the D-arm structure of tRNA^Ser/Leu, while its presence in helices 34 and 45 of 18S rRNA (at positions 1337 and 1842, respectively) is important for rRNA processing. Within mRNA, ac4C influences translation in a position-dependent manner. ac4C generally inhibits translation initiation within 5’UTRs but promotes translation elongation within coding sequences.

Figure 2.. Regulatory functions of NAT10 in human cells.

NAT10 has emerged as a critical regulator of the cell cycle, DNA damage response (DDR), tumorigenesis, cellular development, and immune responses in human cells. This is achieved through acetylation of both protein and RNA substrates, but how these activities are coordinated remains unknown.

Figure 3.. Biological relevance of NAT10 expression.

Various biological processes have been mechanistically linked to variations in NAT10 expression. In human embryonic stem cells, elevated NAT10 levels are required for the maintenance of pluripotency, while the epithelial-mesenchymal-transition (EMT) during tumorigenesis is accompanied by increases in NAT10 expression. During gametogenesis, NAT10 levels decline from an initial high level, and decreases in NAT10 expression are also observed in sepsis.