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癌症细胞中APOBEC3B-介导的RNA编辑的特征揭示NEAT1和MALAT1 lncRNA的调节作用
Characterisation of APOBEC3B-Mediated RNA editing in breast cancer cells reveals regulatory roles of NEAT1 and MALAT1 lncRNAs
Nature 等信源发布 2024-09-25 16:39
可切换为仅中文
AbstractRNA editing is a crucial post-transcriptional process that influences gene expression and increases the diversity of the proteome as a result of amino acid substitution. Recently, the APOBEC3 family has emerged as a significant player in this mechanism, with APOBEC3A (A3A) having prominent roles in base editing during immune and stress responses.
摘要RNA编辑是一个关键的转录后过程，它会影响基因表达，并由于氨基酸取代而增加蛋白质组的多样性。最近，APOBEC3家族已成为该机制的重要参与者，APOBEC3A（A3A）在免疫和应激反应过程中的碱基编辑中起着重要作用。
APOBEC3B (A3B), another family member, has gained attention for its potential role in generating genomic DNA mutations in breast cancer. In this study, we coupled an inducible expression cell model with a novel methodology for identifying differential variants in RNA (DVRs) to map A3B-mediated RNA editing sites in a breast cancer cell model.
APOBEC3B（A3B）是另一个家族成员，因其在乳腺癌中产生基因组DNA突变的潜在作用而备受关注。在这项研究中，我们将诱导型表达细胞模型与用于鉴定RNA（DVR）中差异变体的新方法相结合，以在乳腺癌细胞模型中绘制A3B介导的RNA编辑位点。
Our findings indicate that A3B engages in selective RNA editing including targeting NEAT1 and MALAT1 long non-coding RNAs that are often highly expressed in tumour cells. Notably, the binding of these RNAs sequesters A3B and suppresses global A3B activity against RNA and DNA. Release of A3B from NEAT1/MALAT1 resulted in increased A3B activity at the expense of A3A activity suggesting a regulatory feedback loop between the two family members.
我们的研究结果表明，A3B参与选择性RNA编辑，包括靶向通常在肿瘤细胞中高度表达的NEAT1和MALAT1长非编码RNA。值得注意的是，这些RNA的结合隔离了A3B并抑制了针对RNA和DNA的整体A3B活性。从NEAT1/MALAT1释放A3B导致A3B活性增加，而以A3A活性为代价，这表明两个家族成员之间存在调节反馈回路。
This research substantially advances our understanding of A3B’s role in RNA editing, its mechanistic underpinnings, and its potential relevance in the pathogenesis of breast cancer..
这项研究大大提高了我们对A3B在RNA编辑中的作用，其机制基础及其在乳腺癌发病机制中的潜在相关性的理解。。
IntroductionRNA editing is a dynamic post-transcriptional process that modulates transcript sequences without altering the underlying genomic DNA sequence [1]. It plays a crucial role in expanding proteomic diversity and regulating gene expression in higher eukaryotes. Among the diverse mechanisms of RNA editing, two major types of modifications have been identified: deamination of adenine to inosine (A > I) or cytidine to uracil (C > U).
引言RNA编辑是一种动态的转录后过程，可调节转录序列而不改变潜在的基因组DNA序列。它在高等真核生物中扩大蛋白质组多样性和调节基因表达方面起着至关重要的作用。在RNA编辑的多种机制中，已经鉴定出两种主要类型的修饰：腺嘌呤脱氨为肌苷（A > I）或胞苷脱氨为尿嘧啶（C > U）。
These modifications impact on the cellular proteome as they are read as guanosine and uridine respectively during translation, thereby altering protein sequences encoded by genomic DNA [2, 3].In mammals, the APOBEC (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like) protein family, alongside the activation-induced cytidine deaminase (AICDA), are prominent members of the cytidine deaminases known for their roles in genomic editing and immune response regulation.
。在哺乳动物中，APOBEC（载脂蛋白B mRNA编辑酶，催化多肽样）蛋白家族以及激活诱导的胞苷脱氨酶（AICDA）是胞苷脱氨酶的重要成员，以其在基因组编辑和免疫应答调节中的作用而闻名。
[4]. While AICDA is recognised for its role in C > U mutation of DNA during antibody gene diversification, the APOBEC proteins have gained attention for their broader-spectrum roles in RNA editing [3, 5]. The human APOBEC family comprises ten members, APOBEC1, APOBEC2, and APOBEC4, that have restricted tissue expression, and the APOBEC3 genes that are more widely expressed, though predominantly in immune cells [6].
[4] 。虽然AICDA因其在抗体基因多样化过程中在DNA的C＞U突变中的作用而被认可，但APOBEC蛋白因其在RNA编辑中更广泛的作用而受到关注[3，5]。人类APOBEC家族包括10个成员，APOBEC1，APOBEC2和APOBEC4，它们具有限制性的组织表达，以及更广泛表达的APOBEC3基因，尽管主要在免疫细胞中表达（6）。
Initially characterised for their ability to inhibit retroviruses and transposable elements by deaminating cytidines in single-stranded DNA, recent studies have revealed the involvement of APOBEC3 family members in RNA editing. Physiological conditions, such as interferon stimulation, hypoxia, and cellular crowding, can induce endogenous APOBEC3A (A3A)-mediated C > U RNA editing in monocytes and immune cells [7,8,9].
最初的特征是它们通过使单链DNA中的胞苷脱氨基来抑制逆转录病毒和转座因子的能力，最近的研究表明APOBEC3家族成员参与了RNA编辑。生理条件，如干扰素刺激，缺氧和细胞拥挤，可诱导单核细胞和免疫细胞内源性APOBEC3A（A3A）介导的C＞U RNA编辑[7,8,9]。
The induction of RNA editing by A3A .
A3A诱导RNA编辑。
Data availability
数据可用性
The high through-put sequencing data, together with processed data files, was available on GEO database with accession number GSE245700 and GSE245701.
高通量测序数据以及处理过的数据文件可在GEO数据库中获得，登录号为GSE245700和GSE245701。
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Download referencesAcknowledgementsWe thank Dr. Alexia Hervieu Viches, and Dr. Alexandra Vasile form the Institute of Cancer Research, London, for helpful discussions and contributing to the idea of this work. We are grateful for the Scientific Computing facility at the Institute of Cancer Research, and NeoTrident Technology Ltd.
下载参考文献致谢我们感谢伦敦癌症研究所的Alexia Hervieu Viches博士和Alexandra Vasile博士进行了有益的讨论，并为这项工作的想法做出了贡献。我们感谢癌症研究所和NeoTrident Technology Ltd的科学计算设施。
for providing computational resources and relevant training. This work was financially supported by The Institute of Cancer Research (London, United Kingdom). CZ was sponsored by Shanghai Pujiang Programme (22PJD104), and Science and Technology Commission of Shanghai Municipality (23S11901100).Author informationAuthor notesThese authors contributed equally: Chi Zhang, Yu-Jing Lu.Authors and AffiliationsCentre for Cancer Drug Discovery, The Institute of Cancer Research, London, UKChi Zhang, Bingjie Chen, Costas Mitsopoulos, Olivia Rossanese & Paul A.
提供计算资源和相关培训。这项工作得到了癌症研究所（英国伦敦）的财政支持。CZ由上海浦江计划（22PJD104）和上海市科学技术委员会（23S11901100）赞助。作者信息作者注意到，这些作者做出了同样的贡献：张弛，陆玉静。癌症药物发现的作者和附属机构，伦敦癌症研究所，张UKChi，陈炳杰，Costas Mitsopoulos，Olivia Rossanese＆Paul A。
ClarkeShanghai Institute of Biological Products, Shanghai, ChinaChi Zhang, Mei Wang, Feifei Xiong & Xiuling LiGuangdong Medicine-Engineering Interdisciplinary Technology Research Centre, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, ChinaYu-Jing LuGMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong, ChinaBingjie ChenAuthorsChi ZhangView author publicationsYou can also search for this author in.
中国上海克拉克斯上海生物制品研究所张驰，王梅，熊飞飞和秀玲广东工业大学生物医学与制药科学学院李光东医学工程跨学科技术研究中心，广州，中国广州医科大学生命科学联合学院，广州，广东，中国陈秉杰作者张驰观点作者出版物你也可以在中搜索这位作者。
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PubMed Google ScholarContributionsCZ, XL, OR, and PAC, conceived this study and provided grant support. CZ, YL, MW, FX, and XL conducted the experiments and analysis unless otherwise noted. CZ, YL, and BC, conducted analysis on WGS data. KM provided guidance on data analysis using sequencing data.
PubMed Google ScholarContributionsCZ，XL，OR和PAC构思了这项研究并提供了资助。。CZ，YL和BC对WGS数据进行了分析。KM提供了使用测序数据进行数据分析的指导。
CZ, XL, and PAC prepared the manuscript.Corresponding authorsCorrespondence to.
CZ，XL和PAC准备了手稿。通讯作者通讯。
Xiuling Li or Paul A. Clarke.Ethics declarations
李秀玲或保罗·克拉克。道德宣言
Competing interests
相互竞争的利益
CZ, KM, OR, and PAC are current or past employees of The Institute of Cancer Research, which has a commercial interest in the discovery and development of A3B inhibitors and operates a reward to inventors’ scheme. Separately, CZ, MW, FX, and XL are employees of Shanghai Institute of Biological Products, an entity presently engaged in the commercial development of therapeutic biologics.
CZ，KM，OR和PAC是癌症研究所（Institute of Cancer Research）的现任或前任员工，该研究所对A3B抑制剂的发现和开发具有商业利益，并对发明人的计划进行奖励。另外，CZ、MW、FX和XL是上海生物制品研究所的员工，该研究所目前从事治疗性生物制品的商业开发。
No conflicts of interest have been reported by the remaining authors..
其余作者没有报告利益冲突。。
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Reprints and permissionsAbout this articleCite this articleZhang, C., Lu, YJ., Wang, M. et al. Characterisation of APOBEC3B-Mediated RNA editing in breast cancer cells reveals regulatory roles of NEAT1 and MALAT1 lncRNAs.
转载和许可本文引用本文Zhang，C.，Lu，YJ。，Wang，M。等人。乳腺癌细胞中APOBEC3B介导的RNA编辑的表征揭示了NEAT1和MALAT1 lncRNA的调节作用。
Oncogene (2024). https://doi.org/10.1038/s41388-024-03171-5Download citationReceived: 16 November 2023Revised: 30 August 2024Accepted: 13 September 2024Published: 25 September 2024DOI: https://doi.org/10.1038/s41388-024-03171-5Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.
癌基因（2024）。https://doi.org/10.1038/s41388-024-03171-5Download引文接收日期：2023年11月16日修订日期：2024年8月30日接受日期：2024年9月13日发布日期：2024年9月25日OI：https://doi.org/10.1038/s41388-024-03171-5Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。。
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