DIS3
小结
DIS3编码RNA外泌体复合物的催化亚基，参与RNA加工和质量控制途径。DIS3催化活性由内切核糖核酸（PIN）和3'-5'外核糖核酸（RNB）结构域控制 。DIS3的遗传性改变在结直肠癌中检测到，例如拷贝数增加和mRNA表达增加。最近对黑色素瘤细胞系的研究表明，在DIS3区域过表达和增加的DNA拷贝数可能在结节性黑素瘤细胞的侵袭性表型中发挥作用。相反，已经在多发性骨髓瘤（MM）中描述了DIS3基因中的失功功能突变。最近，MM患者的全基因组（WGS）和外显子组（WES）测序研究数据发现，DIS3基因出现反复突变。在MM患者中鉴定的一些DIS3突变显示干扰了其核酸外切活性，导致异常RNA代谢和细胞系中较慢的增殖速率。此外，DIS3通过降低let-7加工抑制剂LIN28B的稳定性，促进肿瘤抑制因子let-7 miRNA的成熟。通过减少成熟let-7，DIS3增强了let-7靶标如MYC和RAS的翻译，导致肿瘤发生增强。DIS3突变患者的基因表达谱分析鉴定展示了RNA外泌体功能受损的转录特征，这也提高了DIS3在此类病症中作为肿瘤抑制基因的可能性。
DIS3 gene encodes the catalytic subunit of the RNA exosome complex, prominently participating in RNA processing and quality control pathways. DIS3 catalytic activity is governed by the endoribonucleolytic (PIN) and the 3’–5’ exoribonucleolyitic (RNB) domains. DIS3 affects the RNA-processing machinery and genetic alterations of DIS3, such as copy number gains and increased mRNA expression, were recently described in colorectal cancer. Additionally, a recent study in melanoma cell lines showed that overexpression and increased DNA copy number in the region of DIS3 may play a role in the aggressive phenotype of nodular melanoma cells. In contrast, loss-off-function mutations in the DIS3 gene have been described in multiple myeloma (MM), suggesting a possible mechanism to disrupt protein translation. Recently, the DIS3 gene has emerged as recurrently mutated in patients with MM from initial whole-genome (WGS) and exome (WES) sequencing studies. Some DIS3 mutations identified in MM were shown to interfere with its exonucleolytic activity, causing aberrant RNA metabolism and slower proliferation rates in cell lines. Furthermore, DIS3 facilitates the maturation of the tumor suppressor let-7 miRNAs by reducing the stability of LIN28B, an inhibitor of let-7 processing. Through the reduction of mature let-7, DIS3 enhances the translation of let-7 targets such as MYC and RAS, leading to enhanced tumorigenesis. Next-generation sequencing analysis of the DIS3 PIN and RNB domains in purified bone marrow plasma cell (PC) dyscrasia from 164 representative patients, including 130 cases with MM, 24 with primary PC leukemia and 10 with secondary PC leukemia) found DIS3 mutations respectively in 18.5%, 25% and 30% of cases. Gene expression profiling analysis in DIS3-mutated patients identified a transcriptional signature suggestive for impaired RNA exosome function, raising the possibility that DIS3 represents a potential tumor suppressor gene in such disorders.