Details

Autor(en) / Beteiligte

• Liu, Nian
• Dai, Qing
• Zheng, Guanqun
• He, Chuan
• Parisien, Marc
• Pan, Tao

Titel

N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions

Ist Teil von

• Nature (London), 2015-02, Vol.518 (7540), p.560-564

Erscheinungsjahr

2015

Link zum Volltext

Quelle

EBSCOhost Psychology and Behavioral Sciences Collection

Beschreibungen/Notizen

• RNA-binding proteins control many aspects of cellular biology through binding single-stranded RNA binding motifs (RBM) 1 - 3 . However, RBMs can be buried within their local RNA structures 4 - 7 , thus inhibiting RNA-protein interactions. N 6 -methyladenosine (m 6 A), the most abundant and dynamic internal modification in eukaryotic messenger RNA 8 - 19 , can be selectively recognized by the YTHDF2 protein to affect the stability of cytoplasmic mRNAs 15 , but how m 6 A achieves wide-ranging physiological significance needs further exploration. Here we show that m 6 A controls the RNA-structure-dependent accessibility of RBMs to affect RNA-protein interactions for biological regulation; we term this mechanism “m 6 A-switch”. We found that m 6 A alters the local structure in mRNA and long non-coding RNA (lncRNA) to facilitate binding of heterogeneous nuclear ribonucleoprotein C (hnRNP C), an abundant nuclear RNA-binding protein responsible for pre-mRNA processing 20 - 24 . Combining PAR-CLIP and m 6 A/MeRIP approaches enabled us to identify 39,060 m 6 A-switches among hnRNP C binding sites; and global m 6 A reduction decreased hnRNP C binding at 2,798 high confidence m 6 A-switches. We determined that these m 6 A-switch-regulated hnRNP C binding activities affect the abundance as well as alternative splicing of target mRNAs, demonstrating the regulatory role of m 6 A-switches on gene expression and RNA maturation. Our results illustrate how RNA-binding proteins gain regulated access to their RBMs through m 6 A-dependent RNA structural remodeling, and provide a new direction for investigating RNA-modification-coded cellular biology.