2. Academic Validation
  3. m6Am sequesters PCF11 to suppress premature termination and drive neuroblastoma differentiation

m6Am sequesters PCF11 to suppress premature termination and drive neuroblastoma differentiation

  • Mol Cell. 2024 Nov 7;84(21):4142-4157.e14. doi: 10.1016/j.molcel.2024.10.004.
Huihui An 1,  Yifan Hong 2,  Yeek Teck Goh 3,  Casslynn W Q Koh 3,  Shahzina Kanwal 2,  Yi Zhang 2,  Zhaoqi Lu 2,  Phoebe M L Yap 3,  Suat Peng Neo 4,  Chun-Ming Wong 5,  Alice S T Wong 6,  Yang Yu 7,  Jessica Sook Yuin Ho 8,  Jayantha Gunaratne 4,  Wee Siong Sho Goh 9
Affiliations

Affiliations

  • 1 Shenzhen Bay Laboratory, Shenzhen, China; School of Biological Sciences, University of Hong Kong, Hong Kong, China; Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
  • 2 Shenzhen Bay Laboratory, Shenzhen, China.
  • 3 Genome Institute of Singapore, Singapore, Singapore.
  • 4 Institute of Molecular and Cell Biology, Singapore, Singapore.
  • 5 Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
  • 6 School of Biological Sciences, University of Hong Kong, Hong Kong, China.
  • 7 Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 8 Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
  • 9 Shenzhen Bay Laboratory, Shenzhen, China. Electronic address: sho.goh.ws@gmail.com.
PMID: 39481383 DOI: 10.1016/j.molcel.2024.10.004
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.

Keywords

PCF11; m(6)Am; neuroblastoma; premature transcription termination.

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