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M6Am sequesters PCF11 to promote full-length transcription [m6ACE]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254149 | GEO | 2024/10/31

REPOSITORIES: GEO

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

Project description: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.

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Project description:N6,2’-O-dimethyladenosine (m6Am) is an abundant mRNA modification that impacts multiple diseases but its function remains controversial since the m6Am reader is unknown. Using quantitative proteomics, we identified transcriptional terminator PCF11 as a m6Am-specific reader. Direct quantification of mature versus nascent RNAs reveals m6Am does not regulate mRNA stability but promotes nascent transcription. Mechanistically, m6Am functions by sequestering PCF11 away from proximal RNA Pol II. This suppresses PCF11 from dissociating Pol II near transcription start sites, thereby promoting full-length transcription of m6Am-modified RNAs. m6Am’s unique relationship with PCF11 means m6Am function is enhanced when PCF11 is reduced, which occurs during all-trans-retinoic-acid (ATRA) induced neuroblastoma-differentiation therapy. Here, m6Am promotes expression of ATF3, a repressor of the neuroblastoma biomarker MYCN. Depleting m6Am suppresses MYCN-repression in ATRA-treated neuroblastoma and maintains their tumour stem-like properties. Collectively, we characterize m6Am as an anti-terminator RNA modification that suppresses premature termination and modulates neuroblastoma therapeutic response.

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m6Am sequesters PCF11 to promote full-length transcription

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Project description:m6Am sequesters PCF11 to promote full-length transcription [catabolicSLAM]