Comparative Biochemical Studies of Disease-Associated Human Dicer Mutations on Processing of a Pre-microRNA and snoRNA.
Comparative Biochemical Studies of Disease-Associated Human Dicer Mutations on Processing of a Pre-microRNA and snoRNA.
复制标题
疾病相关人类 Dicer 突变对 Pre-microRNA 和 snoRNA 加工的比较生化研究。
DOI：
10.1021/acs.biochem.2c00687
复制
发表时间：
2023-05
期刊：
影响因子：
2.9
通讯作者：
Rachel M. Torrez;S. Nagaraja;Arya Menon;Louise Chang;M. Ohi;A. Garner
中科院分区：
文献类型：
--
作者：
Rachel M. Torrez;S. Nagaraja;Arya Menon;Louise Chang;M. Ohi;A. Garner
Dicer是一种RNase III酶，负责小rna（如microRNAs）的成熟。由于Dicer的裂解产物通过基因表达的微调在促进细胞稳态中起关键作用，Dicer活性的失调可导致包括癌症在内的几种人类疾病。DICER1的突变已被发现可诱导肿瘤发生，并导致一种罕见的多性肿瘤易感性综合征的发展，这种综合征见于儿童和年轻人，称为DICER1综合征。这些患者在Dicer中携带生殖系和体细胞突变，导致microRNA加工和活性缺陷。虽然大多数突变发生在Dicer的催化RNase III结构域内，但Platform-PAZ （Piwi-Argonaute-Zwille）结构域内的改变也会导致microRNA产生的损失。利用体外生化和细胞研究的结合，我们表征了疾病相关平台- paz相关突变对一种已被充分研究的致癌microRNA-21加工的影响。然后，我们将这些结果与另一类Dicer底物（小核仁RNA， snord37）的代表性结果进行了比较。从这一分析中，我们提供了Platform-PAZ结构域内的突变对RNA结合和加工产生不同影响的证据，为小RNA底物的Dicer加工的复杂性提供了新的见解。
Dicer is an RNase III enzyme that is responsible for the maturation of small RNAs such as microRNAs. As Dicer's cleavage products play key roles in promoting cellular homeostasis through the fine-tuning of gene expression, dysregulation of Dicer activity can lead to several human diseases, including cancers. Mutations in Dicer have been found to induce tumorigenesis and lead to the development of a rare pleiotropic tumor predisposition syndrome found in children and young adults called DICER1 syndrome. These patients harbor germline and somatic mutations in Dicer that lead to defective microRNA processing and activity. While most mutations occur within Dicer's catalytic RNase III domains, alterations within the Platform-PAZ (Piwi-Argonaute-Zwille) domain also cause loss of microRNA production. Using a combination of in vitro biochemical and cellular studies, we characterized the effect of disease-relevant Platform-PAZ-associated mutations on the processing of a well-studied oncogenic microRNA, pre-microRNA-21. We then compared these results to those of a representative from another Dicer substrate class, the small nucleolar RNA, snord37. From this analysis, we provide evidence that mutations within the Platform-PAZ domain result in differential impacts on RNA binding and processing, adding new insights into the complexities of Dicer processing of small RNA substrates.