RNA modification in regulation of gene expression and cancer

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  • Writer 최고관리자
  • 2018-11-12


[Life Sciences / IBB Faculty Candidate Seminar]

 ▶Speaker: Choe Junho, Ph.D. (Post-doctoral fellow, Harvard Medical School)

 ▶Date: 4:00PM/Nov. 14(Wed.)/ 2018

▶Place: Auditorium(1F), Postech Biotech Center

N6-Methyladenosine  (m6A),  the  most  abundant  posttranscriptional  messenger  RNA (mRNA)  modification,  is  emerging  as  an  important  regulator  of  gene  expression. Manipulation  of  m6A  impacts  different  developmental  and  biological  processes,  and altered m6A homeostasis is linked to cancer. m6A is catalyzed by METTL3 and enriched in the 3’ untranslated region (3’ UTR) of a large subset of mRNAs at sites close to the stop  codon.  METTL3  can  promote  translation  but  the  mechanism  and  widespread relevance remain unknown. Here we show that METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop codon supporting a mRNA looping mechanism for ribosome recycling and translational control. Electron microscopy reveals the  topology  of  individual  polyribosomes  with  single  METTL3  foci  found  in  close proximity  to  5’  cap-binding  proteins.  We  identify  a  direct  physical  and  functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit h (eIF3h). METTL3 promotes translation of a large subset of oncogenic mRNAs, including Bromodomain-containing  protein  4  (BRD4)  that  are  also  m6A-modified  in  human primary lung tumors. The METTL3-eIF3h interaction is required for enhanced translation, formation  of  densely  packed  polyribosomes,  and  oncogenic  transformation.  METTL3 depletion  inhibits  tumorigenicity  and  sensitizes  lung  cancer  cells  to  BRD4  inhibition. These findings uncover a mRNA looping mechanism of translation control and identify METTL3-eIF3h as a potential cancer therapeutic target.

▶Contact: Department of Life Sciences (Tel. 279-2721)

* This seminar will be given in English.
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