[MerR-seq] The RNA helicase domain of NAT10 promotes the biogenesis of hypomodified ribosomes to enhance cancer cell proliferation

By coupling Proteolysis Targeting Chimera-mediated degradation of NAT10 with a deep mutational scanning assay, followed by biochemical, cellular, and in vivo validations, we find that the RNA helicase domain of NAT10 enhances cancer cell proliferation and tumor growth.

This proliferative function of NAT10 is independent of RNA acetylation but requires its RNA-binding activity. The RNA helicase domain of NAT10 is required for 18S rRNA binding, promoting biogenesis of the 40S ribosomal subunit, while simultaneously interfering with the deposition of the conserved 18S rRNA modification m¹acp³Ψ. Loss of m¹acp³Ψ in 18S rRNA enhances cancer cell proliferation, revealing that NAT10 promotes the biogenesis of hypomodified ribosomes to facilitate tumor growth.