Huihui An, Yifan Hong, Yeek Teck Goh, Casslynn W.Q. Koh, Shahzina Kanwal, Yi Zhang, Zhaoqi Lu, Phoebe M.L. Yap, Suat Peng Neo, Chun-Ming Wong, Alice S.T. Wong, Yang Yu, Jessica Sook Yuin Ho, Jayantha Gunaratne, Wee Siong Sho Goh
{"title":"m6Am sequesters PCF11 to suppress premature termination and drive neuroblastoma differentiation","authors":"Huihui An, Yifan Hong, Yeek Teck Goh, Casslynn W.Q. Koh, Shahzina Kanwal, Yi Zhang, Zhaoqi Lu, Phoebe M.L. Yap, Suat Peng Neo, Chun-Ming Wong, Alice S.T. Wong, Yang Yu, Jessica Sook Yuin Ho, Jayantha Gunaratne, Wee Siong Sho Goh","doi":"10.1016/j.molcel.2024.10.004","DOIUrl":null,"url":null,"abstract":"<em>N</em><sup>6</sup>,2′-O-dimethyladenosine (m<sup>6</sup>Am) is an abundant mRNA modification that impacts multiple diseases, but its function remains controversial because the m<sup>6</sup>Am reader is unknown. Using quantitative proteomics, we identified transcriptional terminator premature cleavage factor II (PCF11) as a m<sup>6</sup>Am-specific reader in human cells. Direct quantification of mature versus nascent RNAs reveals that m<sup>6</sup>Am does not regulate mRNA stability but promotes nascent transcription. Mechanistically, m<sup>6</sup>Am 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 m<sup>6</sup>Am-modified RNAs. m<sup>6</sup>Am’s unique relationship with PCF11 means m<sup>6</sup>Am function is enhanced when PCF11 is reduced, which occurs during all-<em>trans</em>-retinoic-acid (ATRA)-induced neuroblastoma-differentiation therapy. Here, m<sup>6</sup>Am promotes expression of ATF3, which represses neuroblastoma biomarker MYCN. Depleting m<sup>6</sup>Am suppresses MYCN repression in ATRA-treated neuroblastoma and maintains their tumor-stem-like properties. Collectively, we characterize m<sup>6</sup>Am as an anti-terminator RNA modification that suppresses premature termination and modulates neuroblastoma’s therapeutic response.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":14.5000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.molcel.2024.10.004","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
N6,2′-O-dimethyladenosine (m6Am) is an abundant mRNA modification that impacts multiple diseases, but its function remains controversial because the m6Am reader is unknown. Using quantitative proteomics, we identified transcriptional terminator premature cleavage factor II (PCF11) as a m6Am-specific reader in human cells. Direct quantification of mature versus nascent RNAs reveals that m6Am does not regulate mRNA stability but promotes nascent transcription. Mechanistically, m6Am 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 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, which represses neuroblastoma biomarker MYCN. Depleting m6Am suppresses MYCN repression in ATRA-treated neuroblastoma and maintains their tumor-stem-like properties. Collectively, we characterize m6Am as an anti-terminator RNA modification that suppresses premature termination and modulates neuroblastoma’s therapeutic response.
期刊介绍:
Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.