文章：

DICER1：突变，microRNAs和机制

DICER1: mutations, microRNAs and mechanisms

原文发布日期：2014-09-01

DOI: 10.1038/nrc3802

类型: Review Article

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要点：

1. Dicer is a type III cytoplasmic endoribonuclease that is involved in the maturation of several classes of small non-coding RNAs, such as microRNAs.
2. Dicer is involved in the maturation of precursor microRNAs, it loads the derived small RNAs into effector Argonaute proteins, and functions as a scaffold for several interactions in the RNA interference mechanisms.
3. Genetic perturbation of Dicer results in defects affecting functions ranging from embryogenesis, differentiation and homeostasis, to cancer.
4. Dicer adopts an overall 'L' shape. The PAZ and Platform domains bind double-stranded RNA (dsRNA) substrate termini, the RNase III domains each cleave along the dsRNA strands, a spacer linker measures the small RNA end products, and an RNA helicase regulates its substrate recognition and activity.
5. Changes in the expression of DICER1 have been associated with various cancers. In general, reduced expression is observed in many cancers, but the data are inconsistent.
6. Germline loss-of-function mutations in DICER1 are associated with a pleiotropic tumour susceptibility syndrome, characterized by pleuropulmonary blastoma, cystic nephroma and other rare entities. Notably, the non-neoplastic condition multinodular goiter seems to feature prominently.
7. In contrast to the loss-of-function mutations, highly specific missense mutations are found as 'second hits' in the tumours that are associated with germline mutations. These missense mutations are almost entirely limited to the RNase IIIb domain of DICER1.
8. Loss-of-heterozygosity of DICER1 is rare and only seems to be frequently associated with a germline DICER1 mutation in the uncommon brain tumour pineoblastoma.
9. Rare phenotypes, such as pituitary blastoma, may be particularly indicative of biallelic mutations in DICER1.

要点翻译：

1. Dicer是一种III型胞质内核糖核酸内切酶，参与多种小非编码RNA（如microRNA）的成熟过程。
2. 该酶负责介导前体microRNA的成熟，将衍生的小RNA装载至效应蛋白Argonaute中，并在RNA干扰机制中作为多种相互作用的结构支架。
3. Dicer的遗传扰动会导致从胚胎发育、分化与稳态维持到癌症发生等多种功能缺陷。  
4. Dicer整体呈“L”形结构：其PAZ结构域和平台结构域可结合双链RNA末端，两个RNase III结构域分别切割双链RNA链，间隔连接区负责测量小RNA终产物的长度，而RNA解旋酶则调控其底物识别与活性。  
5. DICER1基因的表达改变与多种癌症相关。尽管多数癌症中观察到其表达下调，但现有数据存在矛盾。
6. DICER1的种系功能缺失突变与多效性肿瘤易感综合征相关，其特征包括肺母细胞瘤、囊性肾瘤等罕见病变，其中非肿瘤性病变多结节性甲状腺肿尤为突出。
7. 与功能缺失突变相反，在种系突变相关肿瘤中常发现高度特异性的错义突变作为“二次打击”，这些突变几乎完全局限于DICER1的RNase IIIb结构域。  
8. DICER1的杂合性缺失较为罕见，仅在不常见的松果体母细胞瘤中与种系DICER1突变频繁相关。
9. 罕见表型（如垂体母细胞瘤）可能特别提示DICER1存在双等位基因突变。

英文摘要：

Dicer is central to microRNA-mediated silencing and several other RNA interference phenomena that are profoundly embedded in cancer gene networks. Most recently, both germline and somatic mutations in DICER1 have been identified in diverse types of cancer. Although some of the mutations clearly reduce the dosage of this key enzyme, others dictate surprisingly specific changes in select classes of small RNAs. This Review reflects on the molecular properties of the Dicer enzymes in small RNA silencing pathways, and rationalizes the newly discovered mutations on the basis of the activities and functions of its determinants.

摘要翻译： 

Dicer是microRNA介导沉默及多种嵌入癌症基因网络RNA干扰现象的核心。近期，在多种癌症中均发现DICER1的胚系与体细胞突变。部分突变显著降低该关键酶的剂量，而另一些则对特定小RNA类别产生出人意料的特异性改变。本文回顾小RNA沉默通路中Dicer酶的分子特性，并基于其活性与功能结构域，解析新发现突变的机制。

原文链接：

DICER1: mutations, microRNAs and mechanisms