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次要内含子驻留会造成克隆性造血障碍和多种癌症易感性
2021-04-15 11:31

美国纪念斯隆-凯特琳癌症中心Omar Abdel-Wahab及其小组发现,次要内含子驻留会造成克隆性造血障碍和多种癌症易感性。这一研究成果于2021年4月12日发表在国际学术期刊《自然-遗传学》上。

在本研究中,研究人员发现由ZRSR2缺失导致的次要内含子剪切受损可增强造血干细胞的自我更新。CRISPR筛选模拟了无意链介导的含次要内含子mRNA分子的衰变,这些mRNA分子的剪接由LZTR1介导,LZTR1是RAS相关GTPases调节因子。在RASopathy Noonan综合征中还发现了LZTR1次要内含子保留,该病是由于内含子突变破坏了剪接和多种实体瘤。这些数据揭示了次要内含子可作为造血调节因子,次要内含子中的非编码突变可作为潜在的癌症驱动因子并建立了ZRSR2突变、LZTR1调控和白血病之间的联系。

据了解,大多数真核生物具有两种截然不同的前体mRNA剪接机制:主要剪接体可除去> 99%的内含子;次要剪接体可除去罕见的、进化上保守的内含子。尽管被认为具有重要的调节功能,但次要剪接体的生理功能仍未得到很好的阐述。例如,次要剪接体组分ZRSR2受复发性白血病相关突变的影响,但尚不清楚次要内含子、造血功能和癌症之间的联系。

附:英文原文

Title: Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition

Author: Daichi Inoue, Jacob T. Polaski, Justin Taylor, Pau Castel, Sisi Chen, Susumu Kobayashi, Simon J. Hogg, Yasutaka Hayashi, Jose Mario Bello Pineda, Ettaib El Marabti, Caroline Erickson, Katherine Knorr, Miki Fukumoto, Hiromi Yamazaki, Atsushi Tanaka, Chie Fukui, Sydney X. Lu, Benjamin H. Durham, Bo Liu, Eric Wang, Sanjoy Mehta, Daniel Zakheim, Ralph Garippa, Alex Penson, Guo-Liang Chew, Frank McCormick, Robert K. Bradley, Omar Abdel-Wahab

Issue&Volume: 2021-04-12

Abstract: Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias. Loss of function of the minor spliceosome component ZRSR2 enhances hematopoietic stem cell self-renewal through minor intron retention of its target LZTR1, which is a regulator of RAS-related GTPases. Minor intron retention of LZTR1 was also identified in Noonan syndrome and diverse solid tumor types.

DOI: 10.1038/s41588-021-00828-9

Source: https://www.nature.com/articles/s41588-021-00828-9

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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