APC mutations dysregulate alternative polyadenylation in cancer

IF 10.1 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Genome Biology Pub Date : 2024-10-07 DOI:10.1186/s13059-024-03406-4
Austin M. Gabel, Andrea E. Belleville, James D. Thomas, Jose Mario Bello Pineda, Robert K. Bradley
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Abstract

Alternative polyadenylation (APA) affects most human genes and is recurrently dysregulated in all studied cancers. However, the mechanistic origins of this dysregulation are incompletely understood. We describe an unbiased analysis of molecular regulators of poly(A) site selection across The Cancer Genome Atlas and identify that colorectal adenocarcinoma is an outlier relative to all other cancer subtypes. This distinction arises from the frequent presence of loss-of-function APC mutations in colorectal adenocarcinoma, which are strongly associated with long 3′ UTR expression relative to tumors lacking APC mutations. APC knockout similarly dysregulates APA in human colon organoids. By mining previously published APC eCLIP data, we show that APC preferentially binds G- and C-rich motifs just upstream of proximal poly(A) sites. Lastly, we find that reduced APC expression is associated with APA dysregulation in tumor types lacking recurrent APC mutations. As APC has been previously identified as an RNA-binding protein that preferentially binds 3′ UTRs during mouse neurogenesis, our results suggest that APC promotes proximal poly(A) site use and that APC loss and altered expression contribute to pervasive APA dysregulation in cancers.
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APC 突变会导致癌症中的替代多腺苷酸化失调
交替多腺苷酸化(APA)影响着大多数人类基因,并在所有研究的癌症中反复出现失调。然而,人们对这种失调的机理还不完全清楚。我们描述了对整个《癌症基因组图谱》中多聚(A)位点选择的分子调控因子的无偏见分析,并发现结直肠腺癌相对于所有其他癌症亚型是一个异常值。这种区别是由于结直肠腺癌中经常出现功能缺失的 APC 突变,与缺乏 APC 突变的肿瘤相比,这种突变与长 3′ UTR 表达密切相关。APC 基因敲除同样会导致人类结肠器官组织中的 APA 失调。通过挖掘以前发表的 APC eCLIP 数据,我们发现 APC 会优先结合近端 poly(A) 位点上游的富含 G 和 C 的基序。最后,我们发现在缺乏复发性 APC 突变的肿瘤类型中,APC 表达的减少与 APA 失调有关。我们的研究结果表明,APC 促进了近端 poly(A) 位点的使用,APC 的缺失和表达改变导致了癌症中普遍存在的 APA 失调。
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来源期刊
Genome Biology
Genome Biology Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
21.00
自引率
3.30%
发文量
241
审稿时长
2 months
期刊介绍: Genome Biology stands as a premier platform for exceptional research across all domains of biology and biomedicine, explored through a genomic and post-genomic lens. With an impressive impact factor of 12.3 (2022),* the journal secures its position as the 3rd-ranked research journal in the Genetics and Heredity category and the 2nd-ranked research journal in the Biotechnology and Applied Microbiology category by Thomson Reuters. Notably, Genome Biology holds the distinction of being the highest-ranked open-access journal in this category. Our dedicated team of highly trained in-house Editors collaborates closely with our esteemed Editorial Board of international experts, ensuring the journal remains on the forefront of scientific advances and community standards. Regular engagement with researchers at conferences and institute visits underscores our commitment to staying abreast of the latest developments in the field.
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