近日，新加坡分子与细胞生物学研究所Ernesto Guccione与美国纪念斯隆·凯特琳癌症中心Omar Abdel-Wahab领衔的国际联合研究团队发表了最新研究成果，他们提出了通过抑制蛋白精氨酸甲基化，实现RNA剪接的治疗靶向催化。相关论文发表在2019年8月出版的《癌细胞》上。

研究人员发现，抑制精氨酸的对称或不对称二甲基化，分别由PRMT5和I型蛋白质精氨酸甲基转移酶（PRMTs）介导，降低了剪接保真度，并选择性杀伤了SF-突变体白血病而非野生型。 这些数据鉴定了最可能响应PRMT抑制的癌症的遗传亚群，指出了PRMT5和I型PRMT联合抑制的协同效应，初步讨论了PRMT抑制在癌症中的治疗效果的机制基础。

研究人员表示，编码RNA剪接因子(SFs)基因的癌症相关突变通常发生在白血病以及各种实体肿瘤中，并依赖于野生型剪接。这些观察结果引领临床开展直接抑制难治型白血病患者的剪接体。

附：英文原文

Title: Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation

Author: Jia Yi Fong, Luca Pignata, Pierre-Alexis Goy, Tiziana Bonaldi, Omar Abdel-Wahab, Ernesto Guccione

Issue&Volume: Volume 36 Issue 2

Abstract: Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.

DOI: https://doi.org/10.1016/j.ccell.2019.07.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30330-7