m6Am sequesters PCF11 to promote full-length transcription [PCT]

RNA modifications regulate how RNAs metabolize and function to impact development and diseases. N6,2’-O-dimethyladenosine (m6Am) is one such modification and despite being abundant, m6Am function remains unclear. Here, we identified cleavage and polyadenylation factor, PCF11 as a m6Am-specific binding protein. Direct quantification of mature versus nascent RNAs revealed that m6Am does not regulate mRNA stability but promotes transcription of nascent RNAs. m6Am caused RNA Polymerase II (Pol II) to be more processive when transcribing m6Am-modified RNAs. Rather than PCF11 regulating m6Am-modified RNA, m6Am sequesters PCF11 away from proximal Pol II, suppressing premature dissociation of elongating Pol II and promoting Pol II full-length transcription of m6Am-modified RNAs. This establishes a mechanism through which an RNA modification regulates transcription.