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

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.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Catherine Denicourt其他文献

Catherine Denicourt的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Catherine Denicourt', 18)}}的其他基金

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
  • 财政年份:
    2019
  • 资助金额:
    $ 34.97万
  • 项目类别:
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:
    10115526
  • 财政年份:
    2019
  • 资助金额:
    $ 34.97万
  • 项目类别:

相似海外基金

Applications of Deep Learning for Binding Affinity Prediction
深度学习在结合亲和力预测中的应用
  • 批准号:
    2887848
  • 财政年份:
    2023
  • 资助金额:
    $ 34.97万
  • 项目类别:
    Studentship
Metalloenzyme binding affinity prediction with VM2
使用 VM2 预测金属酶结合亲和力
  • 批准号:
    10697593
  • 财政年份:
    2023
  • 资助金额:
    $ 34.97万
  • 项目类别:
Building a binding community - Capacity and capability for affinity and kinetic analysis of molecular interactions.
建立结合社区 - 分子相互作用的亲和力和动力学分析的能力和能力。
  • 批准号:
    MR/X013227/1
  • 财政年份:
    2022
  • 资助金额:
    $ 34.97万
  • 项目类别:
    Research Grant
Using dynamic network models to quantitatively predict changes in binding affinity/specificity that arise from long-range amino acid substitutions
使用动态网络模型定量预测由长程氨基酸取代引起的结合亲和力/特异性的变化
  • 批准号:
    10797940
  • 财政年份:
    2022
  • 资助金额:
    $ 34.97万
  • 项目类别:
Using dynamic network models to quantitatively predict changes in binding affinity/specificity that arise from long-range amino acid substitutions
使用动态网络模型定量预测由长距离氨基酸取代引起的结合亲和力/特异性的变化
  • 批准号:
    10502084
  • 财政年份:
    2022
  • 资助金额:
    $ 34.97万
  • 项目类别:
Using dynamic network models to quantitatively predict changes in binding affinity/specificity that arise from long-range amino acid substitutions
使用动态网络模型定量预测由长距离氨基酸取代引起的结合亲和力/特异性的变化
  • 批准号:
    10707418
  • 财政年份:
    2022
  • 资助金额:
    $ 34.97万
  • 项目类别:
Binding affinity of inositol phosphate analogs to protein toxin TcdB
磷酸肌醇类似物与蛋白质毒素 TcdB 的结合亲和力
  • 批准号:
    573604-2022
  • 财政年份:
    2022
  • 资助金额:
    $ 34.97万
  • 项目类别:
    University Undergraduate Student Research Awards
Computational predictions of thermostability and binding affinity changes in enzymes
酶热稳定性和结合亲和力变化的计算预测
  • 批准号:
    2610945
  • 财政年份:
    2021
  • 资助金额:
    $ 34.97万
  • 项目类别:
    Studentship
I-Corps: Physics-Based Binding Affinity Estimator
I-Corps:基于物理的结合亲和力估计器
  • 批准号:
    2138667
  • 财政年份:
    2021
  • 资助金额:
    $ 34.97万
  • 项目类别:
    Standard Grant
Computational modelling and simulation of antibodies to enhance binding affinity of a potential Burkholderia pseudomallei therapeutic
抗体的计算模型和模拟,以增强潜在的鼻疽伯克霍尔德氏菌治疗剂的结合亲和力
  • 批准号:
    2750554
  • 财政年份:
    2021
  • 资助金额:
    $ 34.97万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了