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

基本信息

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
项目类别：
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

项目摘要

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 mRNA翻译的保真度对于维持细胞稳态至关重要可能导致疾病发展的异常蛋白质。核糖体是核心的关键组成部分翻译机械的活性可以通过在核糖体RNA（rRNA）。越来越多的证据表明，rRNA甲基化的模式在癌症，导致合成专业核糖体具有转换mRNA编码的独特能力用于致癌蛋白。 rRNA甲基化已显示可动态调节核糖体功能，并且影响他们对某些类型的mRNA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。我们的总体目标是确定参与调节异常的途径和关键参与者癌症中rRNA的甲基化表示未开发的治疗靶标。我们最近发现了癌基因PELP1是癌细胞中rRNA甲基化的重要调节剂。我们的实验方法，由初步数据支持的是阐明PELP1调节rRNA甲基化和证明了这一过程对癌症进展的重要性。我们假设PELP1支持肿瘤发生通过调节RRNA甲基化的能力来调节核糖体转化活性。在 AIM1我们将确定PELP1是否通过募集RNA甲基转移酶为新生的rRNA转录本。因为rRNA甲基化在调节翻译中起着重要作用核糖体的能力，我们将评估PELP1的过表达是否会改变核糖体效率，保真度，使用翻译记者分析和多元素分析 - 对某些类型的mRNA的亲和力 - 方法（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等级，转移和内分泌疗法耐药性相关。在AIM 3中，我们将使用原位乳腺癌的小鼠模型评估PELP1是否需要调节rRNA甲基化的能力支持肿瘤发生。我们的发现表明，通过调节rRNA甲基化，PELP1参与癌细胞的翻译重编程，从而促进了致癌基因的选择性翻译。这成功完成我们提出的研究将产生对异常mRNA机制的重要见解翻译及其在肿瘤发生中的作用。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.

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