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摘要 : N6-methyladenosine (m6A) 是很多真核mRNAs和长非编码RNAs中一种常见内部修饰。它涉及包括生物节律、减数分裂和干细胞发育在内的各种细胞功能的控制。

 N6-methyladenosine (m6A) 是很多真核mRNAs和长非编码RNAs中一种常见内部修饰。它涉及包括生物节律、减数分裂和干细胞发育在内的各种细胞功能的控制。

这项研究揭示了m6A 调控RNA–蛋白质相互作用的一个以前人们不知道的机制。

Tao Pan及同事发现,很多 “RNA结合蛋白”(RBPs)的结合基序正常情况下埋在它们的结构化区域内。m6A 修饰起一个开关的作用,来重新组织这些区域,诱导使该基序曝露、从而促进RBP结合的结构变化。

这一发现表明,m6A 充当一个RNA结构重塑器(remodeller)的作用,比如说通过干扰转录后调控因子的结合活性来影响mRNA成熟。


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

RNA-binding proteins control many aspects of cellular biology through binding single-stranded RNA binding motifs (RBMs)1, 2, 3. However, RBMs can be buried within their local RNA structures4, 5, 6,7, thus inhibiting RNA–protein interactions. N6-methyladenosine (m6A), the most abundant and dynamic internal modification in eukaryotic messenger RNA8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, can be selectively recognized by the YTHDF2 protein to affect the stability of cytoplasmic mRNAs15, but how m6A achieves its wide-ranging physiological role needs further exploration. Here we show in human cells that m6A controls the RNA-structure-dependent accessibility of RBMs to affect RNA–protein interactions for biological regulation; we term this mechanism ‘the m6A-switch’. We found that m6A alters the local structure in mRNA and long non-coding RNA (lncRNA) to facilitate binding of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an abundant nuclear RNA-binding protein responsible for pre-mRNA processing20, 21, 22, 23, 24. Combining photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) and anti-m6A immunoprecipitation (MeRIP) approaches enabled us to identify 39,060 m6A-switches among HNRNPC-binding sites; and global m6A reduction decreased HNRNPC binding at 2,798 high-confidence m6A-switches. We determined that these m6A-switch-regulated HNRNPC-binding activities affect the abundance as well as alternative splicing of target mRNAs, demonstrating the regulatory role of m6A-switches on gene expression and RNA maturation. Our results illustrate how RNA-binding proteins gain regulated access to their RBMs through m6A-dependent RNA structural remodelling, and provide a new direction for investigating RNA-modification-coded cellular biology.


Molecular biology: RNA modification does a regulatory two-step

The m6A structural modification of RNA regulates gene expression. It has now been found to mediate an unusual control mechanism: by altering the structure of RNA, m6A allows a regulatory protein to bind to that RNA.


对应Nature杂志: 2015年02月26日Nature杂志精选

来源: Nature 浏览次数:148


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