Mechanisms of aberrant ribosomal RNA (rRNA) methylation and altered mRNA translation in cancers

癌症中异常核糖体 RNA (rRNA) 甲基化和 mRNA 翻译改变的机制

• 批准号: 10552554
• 负责人: Catherine Denicourt
• 金额: $ 34.97万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552554
• 关键词: Affect; Affinity; Binding; Biogenesis; Bioinformatics; Biological Assay; Breast Cancer Model; Catalytic Domain; Cells; Code; Complex; Data; Development; Disease; Environment; Frequencies; Future; Genes; Genetic Transcription; Goals; Homeostasis; Human; Impairment; Malignant Neoplasms; Mass Spectrum Analysis; Medical center; Messenger RNA; Methylation; Methyltransferase; Molecular; Molecular Machines; Neoplasm Metastasis; Nucleotides; Oncogenes; Oncogenic; Pathway interactions; Pattern; Peptidyltransferase; Play; Process; Production; Proteins; Proteome; Qualifying; RNA; RNA chemical synthesis; RNA methylation; Reporter; Resistance; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; Shapes; Specificity; Testing; Texas; Therapeutic Intervention; Transcript; Transcription Process; Translating; Translations; Tumor Promotion; breast cancer progression; cancer cell; fibrillarin; hormone therapy; insight; mRNA Translation; malignant breast neoplasm; medical schools; metaplastic cell transformation; methylation pattern; mouse model; novel; novel therapeutics; overexpression; polysome profiling; prevent; protein complex; public health relevance; recruit; therapeutic development; therapeutic target; tumor; tumor progression; tumorigenesis

Project Summary The fidelity of mRNA translation is essential to maintain cellular homeostasis and prevent the production of aberrant proteins that could lead to disease development. Ribosomes are key components of the core translational machinery whose activity can be modulated by diverse types of nucleotide methylation on the ribosomal RNA (rRNA). A growing body of evidence indicates that the pattern of rRNA methylation is altered in cancers, leading to the synthesis of specialized ribosomes with the unique ability to translate mRNAs coding for oncogenic proteins. rRNA methylation has been shown to dynamically regulate ribosome function and influence their efficiency, accuracy and affinity for certain type of mRNAs. Hence, pathways regulating rRNA methylation can selectively drive the translation of a proteome that supports cellular transformation and tumor development. Our overarching goal is to identify pathways and key players involved in regulating the aberrant methylation of rRNA in cancers as they represent unexploited therapeutics targets. We recently uncovered that the oncogene Pelp1 is an important regulator of rRNA methylation in cancer cells. Our experimental approach, supported by preliminary data, is to elucidate the mechanisms by which Pelp1 regulates rRNA methylation and demonstrate the importance of this process for cancer progression. We hypothesize that Pelp1 supports tumorigenesis by modulating ribosomes translational activity through its ability to regulate rRNA methylation. In Aim1 we will determine whether Pelp1 regulates rRNA methylation by recruiting RNA methyltransferases to the nascent rRNA transcript. Because rRNA methylation plays an important role in regulating the translational capacity of ribosomes, we will assess whether overexpression of Pelp1 changes ribosome efficiency, fidelity, and affinity for certain types of mRNAs using translation reporter assays and a polysome profiling-sequencing approach (Aim 2). Pelp1 is overexpressed in 60-80% of breast cancers, where its level of expression directly correlates with tumor grade, metastasis, and endocrine therapy resistance. In Aim 3, we will use orthotopic mouse model of breast cancer to assess whether the ability of Pelp1 to regulate rRNA methylation is required to support tumorigenesis. Our findings suggest that by regulating rRNA methylation, Pelp1 participates in the translational reprograming of cancer cells, thereby promoting the selective translation of oncogenic genes. The successful completion of our proposed study will yield important insight into mechanisms of aberrant mRNA translation and it roles in oncogenesis.

项目摘要 信使核糖核酸翻译的保真度对于维持细胞内环境的稳定和防止产生 可能导致疾病发展的异常蛋白质。核糖体是核心的关键成分 翻译机制，其活性可以被不同类型的核苷酸甲基化所调节 核糖体RNA(RRNA)。越来越多的证据表明，rRNA甲基化模式在 癌症，导致合成专门的核糖体，具有翻译编码mRNAs的独特能力 致癌蛋白。RRNA甲基化已被证明可以动态调节核糖体功能和 影响它们对某些类型的mRNAs的效率、准确性和亲和力。因此，调节rRNA的途径 甲基化可以选择性地驱动支持细胞转化和肿瘤的蛋白质组的翻译 发展。我们的首要目标是确定参与调控异常的途径和关键角色 癌症中rRNA的甲基化，因为它们代表未开发的治疗靶点。我们最近发现 癌基因Pelp1是癌细胞中rRNA甲基化的重要调节因子。我们的实验方法， 在初步数据的支持下，阐明了Pelp1调节rRNA甲基化和 证明这一过程对癌症进展的重要性。我们假设Pelp1支持 肿瘤发生是通过调节rRNA甲基化来调节核糖体的翻译活性。在……里面 我们将确定Pelp1是否通过招募RNA甲基转移酶来调节rRNA甲基化 新生的rRNA转录本。因为rRNA甲基化在调节翻译过程中起着重要作用。 我们将评估Pelp1的过表达是否改变了核糖体的效率，保真度， 以及利用翻译报告分析和多聚体分析-测序对特定类型的mRNAs的亲和力 接近(目标2)。Pelp1在60%-80%的乳腺癌中过表达，其表达水平直接 与肿瘤分级、转移和内分泌治疗抵抗有关。在目标3中，我们将使用正位法 用小鼠乳腺癌模型评估是否需要Pelp1调节rRNA甲基化的能力 以支持肿瘤的发生。我们的发现表明，通过调节rRNA甲基化，Pelp1参与了 癌细胞的翻译重编程，从而促进致癌基因的选择性翻译。这个 我们建议的研究的成功完成将为异常mRNA的机制提供重要的见解 翻译及其在肿瘤发生中的作用。

项目成果

p53 induces a survival transcriptional response after nucleolar stress.

• DOI: 10.1091/mbc.e21-05-0251
• 发表时间: 2021-10-01
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Liao H;Gaur A;Mauvais C;Denicourt C
• 通讯作者: Denicourt C

Human NOP2/NSUN1 regulates ribosome biogenesis through non-catalytic complex formation with box C/D snoRNPs.

人NOP2/NSUN1通过与盒子C/D snornps的非催化复合物形成来调节核糖体生物发生。

• DOI: 10.1093/nar/gkac817
• 发表时间: 2022-10-14
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Liao, Han;Gaur, Anushri;McConie, Hunter;Shekar, Amirtha;Wang, Karen;Chang, Jeffrey T.;Breton, Ghislain;Denicourt, Catherine
• 通讯作者: Denicourt, Catherine