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癌症中U1剪接体RNA发生高频突变
2019-10-10 16:50

加拿大多伦多大学Lincoln D. Stein研究组研究显示,U1剪接体RNA在多种癌症中发生突变。该项研究成果在线发表于2019年10月9日的《自然》。

他们报告了在几种肿瘤类型中,U1 snRNA的第三个碱基处高频出现的A>C体细胞突变。 U1的主要功能是通过碱基配对识别5'剪接位点(5'SS)。此突变将U1和5'SS之间的优先A-U碱基配对更改为C-G碱基配对,从而创建新的剪接点并改变了多个基因的剪接模式,包括已知的癌症驱动程序。

在临床上,A>C突变与肝细胞癌(HCC)的酗酒和慢性淋巴细胞性白血病(CLL)的侵袭性IGHV基因未突变亚型相关。U1突变还可以使CLL患者独立接受不良预后。他们的研究证明了剪接体RNA中最早的非编码驱动程序之一,揭示了癌症中异常剪接的新机制,可能代表了新的治疗靶标。他们的发现还表明,驱动程序的发现应扩展到更广泛的基因组区域。

据悉,癌症是由称为驱动因子的基因组改变引起的。已知有数百种编码基因的驱动程序,但尽管进行了深入的搜索,但迄今为止仅发现了少数非编码驱动程序。最近注意力已经转移到改变的RNA剪接在癌症中的作用。尽管仅在蛋白质编码剪接因子(如SF3B1(剪接因子3b亚基1))中发现了导致多种转录类型的异常剪接的驱动子突变,但仍在多种癌症类型中得到了证实。相比之下,由于表征非编码癌症驱动程序的综合挑战和snRNA基因的重复性,对剪接体非编码成分,一系列小核RNA(snRNA)的癌症相关改变的研究很少。

附:英文原文

Title: The U1 spliceosomal RNA is recurrently mutated in multiple cancers

Author: Shimin Shuai, Hiromichi Suzuki, Ander Diaz-Navarro, Ferran Nadeu, Sachin A. Kumar, Ana Gutierrez-Fernandez, Julio Delgado, Magda Pinyol, Carlos Lpez-Otn, Xose S. Puente, Michael D. Taylor, Elas Campo, Lincoln D. Stein

Issue&Volume: 2019-10-09

Abstract: 

Cancers are caused by genomic alterations known as drivers. While hundreds of drivers in coding genes are known, only a handful of non-coding drivers have been discovered to date despite intensive searching1,2. Attention has recently shifted to the role of altered RNA splicing in cancer; driver mutations that lead to transcriptome-wide aberrant splicing have been identified in multiple cancer types, although they have only been found in protein-coding splicing factors like SF3B1 (splicing factor 3b subunit 1)3–6. In contrast, cancer-related alterations in the non-coding component of the spliceosome, a series of small nuclear RNAs (snRNAs), have barely been studied due to the combined challenges of characterizing non-coding cancer drivers and the repetitive nature of snRNA genes1,7,8. Here we report a highly recurrent A>C somatic mutation at the third base of U1 snRNA in several tumour types. The primary function of U1 is to recognize the 5′ splice site (5′SS) via base-pairing. This mutation changes the preferential A-U base-pairing between U1 and 5′SS to C-G base-pairing, thereby creating novel splice junctions and altering the splicing pattern of multiple genes, including known cancer drivers. Clinically, the A>C mutation is associated with alcohol abuse in hepatocellular carcinoma (HCC) and the aggressive IGHV unmutated subtype of chronic lymphocytic leukaemia (CLL). The U1 mutation also confers an adverse prognosis to CLL patients independently. Our study demonstrates one of the first non-coding drivers in spliceosomal RNAs, reveals a novel mechanism of aberrant splicing in cancer and may represent a new target for treatment. Our findings also suggest that driver discovery should be extended to a wider range of genomic regions.

DOI: 10.1038/s41586-019-1651-z

Source:https://www.nature.com/articles/s41586-019-1651-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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