摘要
RNA编辑是发生于双链RNA(dsRNA)上的一类重要转录后反应,可通过碱基插入、缺失或替换的方式改变RNA的核苷酸序列从而丰富转录组和蛋白质组水平的多样性.哺乳动物中最常见的RNA编辑是ADAR家族介导的腺嘌呤-次黄嘌呤编辑(A-to-I),其在碱基配对过程中被识别为鸟嘌呤.人类转录组中已报道了数百万个A-to-I编辑位点,而ADAR1是最主要的催化酶.在血液肿瘤中,ADAR1的失调将直接影响基因编码区、非编码区和miRNA前体的A-to-I编辑状态,从而导致一系列分子事件改变,如蛋白质编码序列改变、内含子滞留、选择性剪接和miRNA生物发生受抑制.近年来研究发现,异常的RNA编辑导致分子调控网络的紊乱,促进细胞增殖、凋亡受阻和细胞耐药,是白血病干细胞(LSCs)生成和干性维持的重要因素.目前,以RNA编辑为靶点的新药(如rebecsinib)已经在动物实验中取得良好疗效.有别于传统抗肿瘤药,表观遗传抗肿瘤药有望克服血液肿瘤的耐药、复发难题,为患者提供全新治疗选择.本综述总结了ADAR1介导的RNA编辑在血液肿瘤中的作用机制及其生物学功能研究的进展,并探讨了其在药物研发和临床应用中的价值.
Abstract
RNA editing,an essential post-transcriptional reaction occurring in double-stranded RNA(dsRNA),generates informational diversity in the transcriptome and proteome.In mammals,the main type of RNA editing is the conversion of adenosine to inosine(A-to-I),processed by adenosine deaminases acting on the RNAs(ADARs)family,and interpreted as guanosine during nucleotide base-pairing.It has been reported that millions of nucleotide sites in human transcriptome undergo A-to-I editing events,catalyzed by the primarily responsible enzyme,ADAR1.In hematological malignancies including myeloid/lymphocytic leukemia and multiple myeloma,dysregulation of ADAR1 directly impacts the A-to-I editing states occurring in coding regions,non-coding regions,and immature miRNA precursors.Subsequently,aberrant A-to-I editing states result in altered molecular events,such as protein-coding sequence changes,intron retention,alternative splicing,and miRNA biogenesis inhibition.As a vital factor of the generation and stemness maintenance in leukemia stem cells(LSCs),disordered RNA editing drives the chaos of molecular regulatory network and ultimately promotes the cell proliferation,apoptosis inhibition and drug resistance.At present,novel drugs designed to target RNA editing(e.g.,rebecsinib)are under development and have achieved outstanding results in animal experiments.Compared with traditional antitumor drugs,epigenetic antitumor drugs are expected to overcome the shackle of drug resistance and recurrence in hematological malignancies,and provide new treatment options for patients.This review summarized the recent advances in the regulation mechanism of ADAR 1-mediated RNA editing events in hematologic malignancies,and further discussed the medical potential and clinical application of ADAR1.
基金项目
国家自然科学基金(82100182)
国家重点研发计划(2022YFA1103300)
重庆市科卫联合医学科研项目(2022DBXM003)
陆军军医大学临床医学科研项目(2018XLC1006)
NETL
NSTL
万方数据