N,2'-O-dimethyladenosine (mAm) is an abundant mRNA modification that impacts multiple diseases, but its function remains controversial because the mAm reader is unknown. Using quantitative proteomics, we identified transcriptional terminator premature cleavage factor II (PCF11) as a mAm-specific reader in human cells. Direct quantification of mature versus nascent RNAs reveals that mAm does not regulate mRNA stability but promotes nascent transcription. Mechanistically, mAm functions by sequestering PCF11 away from proximal RNA polymerase II (RNA Pol II). This suppresses PCF11 from dissociating RNA Pol II near transcription start sites, thereby promoting full-length transcription of mAm-modified RNAs. mAm's unique relationship with PCF11 means mAm function is enhanced when PCF11 is reduced, which occurs during all-trans-retinoic-acid (ATRA)-induced neuroblastoma-differentiation therapy. Here, mAm promotes expression of ATF3, which represses neuroblastoma biomarker MYCN. Depleting mAm suppresses MYCN repression in ATRA-treated neuroblastoma and maintains their tumor-stem-like properties. Collectively, we characterize mAm as an anti-terminator RNA modification that suppresses premature termination and modulates neuroblastoma's therapeutic response.

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http://dx.doi.org/10.1016/j.molcel.2024.10.004DOI Listing

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