RNA剪接
三核苷酸重复扩增
翻译(生物学)
遗传学
打开阅读框
生物
阅读框
直接重复
跑
起始密码子
选择性拼接
RNA结合蛋白
剪接
终止密码子
核糖核酸
细胞生物学
信使核糖核酸
基因
肽序列
基因组
等位基因
作者
Rachel Anderson,Michael R. Das,Yeonji Chang,Kelsey Farenhem,Ankur Jain
标识
DOI:10.1101/2023.10.16.562581
摘要
Expansions of CAG trinucleotide repeats cause several rare neurodegenerative diseases. The disease-causing repeats are translated in multiple reading frames, without an identifiable initiation codon. The molecular mechanism of this repeat-associated non-AUG (RAN) translation is not known. We find that expanded CAG repeats create new splice acceptor sites. Splicing of proximal donors to the repeats produces unexpected repeat-containing transcripts. Upon splicing, depending on the sequences surrounding the donor, CAG repeats may become embedded in AUG-initiated open reading frames. Canonical AUG-initiated translation of these aberrant RNAs accounts for proteins that are attributed to RAN translation. Disruption of the relevant splice donors or the in-frame AUG initiation codons is sufficient to abrogate RAN translation. Our findings provide a molecular explanation for the abnormal translation products observed in CAG trinucleotide repeat expansion disorders and add to the repertoire of mechanisms by which repeat expansion mutations disrupt cellular functions.
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