Rudich Paige, Lamitina Todd
Graduate Program in Cell Biology and Molecular Physiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.
J Genet. 2018 Jul;97(3):665-677.
The inappropriate genetic expansion of various repetitive DNA sequences underlies over 20 distinct inherited diseases. The genetic context of these repeats in exons, introns and untranslated regions has played a major role in thinking about the mechanisms by which various repeat expansions might cause disease. Repeat expansions in exons are thought to give rise to expanded toxic protein repeats (i.e. polyQ). Repeat expansions in introns and UTRs (i.e. FXTAS) are thought to produce aberrant repeat-bearing RNAs that interact with and sequester a wide variety of essential proteins, resulting in cellular toxicity. However, a new phenomenon termed 'repeat-associated nonAUG dependent (RAN) translation' paints a new and unifying picture of how distinct repeat expansion-bearing RNAs might act as substrates for this noncanonical form of translation, leading to the production of a wide range of repeat sequence-specific-encoded toxic proteins. Here, we review how the model system has been utilized to model many repeat disorders and discuss how RAN translation could be a previously unappreciated contributor to the toxicity associated with these different models.
各种重复DNA序列的不适当遗传扩增是20多种不同遗传性疾病的基础。这些重复序列在外显子、内含子和非翻译区的遗传背景，在思考各种重复扩增可能导致疾病的机制方面发挥了重要作用。外显子中的重复扩增被认为会导致毒性蛋白重复序列（即polyQ）的扩增。内含子和非翻译区（即FXTAS）中的重复扩增被认为会产生异常的携带重复序列的RNA，这些RNA与多种必需蛋白相互作用并隔离它们，从而导致细胞毒性。然而，一种名为“重复相关非AUG依赖（RAN）翻译”的新现象，为携带不同重复扩增的RNA如何作为这种非经典翻译形式的底物提供了一个新的统一图景，导致产生各种重复序列特异性编码的毒性蛋白。在这里，我们回顾了模型系统如何被用于模拟许多重复序列疾病，并讨论了RAN翻译如何可能是与这些不同模型相关的毒性的一个以前未被认识到的因素。
