3' untranslated region somatic variants connect alternative polyadenylation dysregulation in human cancers.

IF 6.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Genetics and Genomics Pub Date : 2025-03-17 DOI:10.1016/j.jgg.2025.03.006

Qiushi Xu, Xiaomeng Cheng, Qianru Li, Peng Yu, Xiaolan Zhou, Yu Chen, Limin Lin, Ting Ni, Zhaozhao Zhao

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引用次数: 0

Abstract

Somatic variants in the cancer genome influence gene expression through diverse mechanisms depending on their specific locations. However, a systematic evaluation of the effects of somatic variants located in 3' untranslated regions (3' UTRs) on alternative polyadenylation (APA) of mRNA remains lacking. In this study, we analyze 10,199 tumor samples across 32 cancer types and identify 1333 somatic single nucleotide variants (SNVs) associated with abnormal 3' UTR APA. Mechanistically, these 3' UTR SNVs can alter cis-regulatory elements, such as the poly(A) signal and UGUA motif, leading to changes in APA. Minigene assays confirm that 3' UTR SNVs in multiple genes, including RPS23 and CHTOP, induce aberrant APA. Among affected genes, 62 exhibit differential stability between tandem 3' UTR isoforms, including HSPA4 and UCK2, validated by experimental assays. Finally, we establish that SNV-related abnormal APA usage serves as an additional layer of expression regulation for tumor-suppressor gene HMGN2 in breast cancer. Collectively, this study reveals 3' UTR APA as a critical mechanism mediating the functional impact of somatic noncoding variants in human cancers.

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3'非翻译区体细胞变异与人类癌症中选择性多腺苷酸化失调有关。

癌症基因组中的体细胞变异根据其特定位置通过多种机制影响基因表达。然而，关于位于3‘非翻译区（3’ utr）的体细胞变异对mRNA的选择性多聚腺苷化（APA）的影响的系统评估仍然缺乏。在这项研究中，我们分析了32种癌症类型的10199个肿瘤样本，发现了1333个与3' UTR APA异常相关的体细胞单核苷酸变异（snv）。从机制上讲，这些3' UTR snv可以改变顺式调控元件，如poly(A)信号和UGUA基序，从而导致APA的变化。Minigene实验证实，包括RPS23和CHTOP在内的多个基因中的3' UTR snv可诱导APA异常。在受影响的基因中，62个在串联3' UTR异构体之间表现出不同的稳定性，包括HSPA4和UCK2，实验分析证实了这一点。最后，我们确定snv相关的APA异常使用可作为乳腺癌肿瘤抑制基因HMGN2的额外表达调控层。总的来说，这项研究揭示了3' UTR APA是介导人类癌症中体细胞非编码变异功能影响的关键机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Genetics and Genomics 生物-生化与分子生物学

CiteScore

8.20

自引率

3.40%

发文量

4756

审稿时长

14 days

期刊介绍： The Journal of Genetics and Genomics (JGG, formerly known as Acta Genetica Sinica ) is an international journal publishing peer-reviewed articles of novel and significant discoveries in the fields of genetics and genomics. Topics of particular interest include but are not limited to molecular genetics, developmental genetics, cytogenetics, epigenetics, medical genetics, population and evolutionary genetics, genomics and functional genomics as well as bioinformatics and computational biology.