Defining Genome Stability Mechanisms and their Regulation by SUMO and Ubiquitin

SUMO 和泛素定义基因组稳定性机制及其调控

基本信息

  • 批准号:
    10687242
  • 负责人:
  • 金额:
    $ 68.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-01 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Maintaining genetic integrity is crucial for cell viability and disease suppression. Consequently, cellular machinery such as the DNA damage response (DDR) has evolved to combat continual genotoxic insults. Whilst specific DNA repair mechanisms have been defined in great detail, understanding the spatiotemporal regulation of DDR factors in the cell remains a key challenge. Here, the covalent postranslational modifiers (PTMs) SUMO and ubiquitin play critical roles, both recruiting DDR proteins to DNA lesions, and then removing them as necessary to promote repair. Indeed, defects in the SUMO and ubiquitin pathways cause failed DDR orchestration, severe genetic instability, and disease. Therefore, the overarching goal of our research is to delineate SUMO and ubiquitin mediated mechanisms that maintain genome integrity, with an eye to identifying and exploiting potential therapeutic avenues. Our proposal centers on two factors, STUbL and SMC5/6, which integrate signaling through SUMO and ubiquitin to support key health-related processes. Of note, STUbL mediates the therapeutic effects of arsenic trioxide in leukemia, and SMC5/6 mutations cause severe disease. STUbL is an E3 ubiquitin ligase that selectively recognizes and ubiquitinates SUMOylated proteins to promote their degradation and/or extraction from chromatin. SMC5/6 is functionally related to cohesin and condensin but uniquely, can modify targets with SUMO and ubiquitin. To provide functional insights, we used proximity labeling to reliably map the proteomic environments of STUbL and SMC5/6 in key health-related settings such as: dysfunctional telomeres, DNA repair, and viral replication. Surprisingly, considerable overlap was identified between each proteome, creating further synergy and efficiency in our research. For example, the functions and targets of SMC5/6 and STUbL intersect in the “alternative lengthening of telomeres” (ALT) pathway used in ~15% of cancers. Thus, we would define STUbL and SMC5/6 roles in the elongation and “trimming” of telomeres through the novel ALT-specific targets and cofactors we identified. In addition, a wealth of recent data supports our hypothesis that STUbL controls SUMO pathway homeostasis, as well as specific targets, to support genome stability, DNA replication, and cell survival. Further analysis using genetic manipulation of the SUMO pathway (e.g. CRISPR/Cas9), mediators of SUMO chain toxicity, and new STUbL targets would establish this key paradigm in SUMO and ubiquitin pathway crosstalk. We also recently identified an SMC5/6 cofactor that binds SUMO and directs the complex to phase-separated ALT PML nuclear bodies, sites of viral replication, and likely DNA lesions, thereby unifying these seemingly disparate processes. Hence, we would define functions for SMC5/6 and its new SUMO binding cofactor in each of these processes to reveal common mechanisms. Overall, our collaborative teams' analysis of STUbL and SMC5/6 using proteomic, genetic, cell biological, biochemical, and biophysical methods would synergize to define key health-related mechanisms at the nexus of the SUMO and ubiquitin pathways; providing targets and guidance for therapeutic interventions.
维持遗传完整性对细胞活力和疾病抑制至关重要。因此,细胞

项目成果

期刊论文数量(0)
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MICHAEL N BODDY其他文献

MICHAEL N BODDY的其他文献

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{{ truncateString('MICHAEL N BODDY', 18)}}的其他基金

Defining Genome Stability Mechanisms and their Regulation by SUMO and Ubiquitin
SUMO 和泛素定义基因组稳定性机制及其调控
  • 批准号:
    10468755
  • 财政年份:
    2020
  • 资助金额:
    $ 68.78万
  • 项目类别:
Defining Genome Stability Mechanisms and their Regulation by SUMO and Ubiquitin
SUMO 和泛素定义基因组稳定性机制及其调控
  • 批准号:
    10241241
  • 财政年份:
    2020
  • 资助金额:
    $ 68.78万
  • 项目类别:
Role of TZAP in telomere homoeostasis
TZAP 在端粒稳态中的作用
  • 批准号:
    9889147
  • 财政年份:
    2017
  • 资助金额:
    $ 68.78万
  • 项目类别:
SUMO-dependent Regulation of Ubiquitin Ligases in Genomic Stability
基因组稳定性中泛素连接酶的 SUMO 依赖性调节
  • 批准号:
    8996575
  • 财政年份:
    2009
  • 资助金额:
    $ 68.78万
  • 项目类别:
SUMO-dependent Regulation of Ubiquitin Ligases in Genomic Stability
基因组稳定性中泛素连接酶的 SUMO 依赖性调节
  • 批准号:
    7753884
  • 财政年份:
    2009
  • 资助金额:
    $ 68.78万
  • 项目类别:
SUMO-dependent Regulation of Ubiquitin Ligases in Genomic Stability
基因组稳定性中泛素连接酶的 SUMO 依赖性调节
  • 批准号:
    8024521
  • 财政年份:
    2009
  • 资助金额:
    $ 68.78万
  • 项目类别:
SUMO-dependent Regulation of Ubiquitin Ligases in Genomic Stability
基因组稳定性中泛素连接酶的 SUMO 依赖性调节
  • 批准号:
    8206797
  • 财政年份:
    2009
  • 资助金额:
    $ 68.78万
  • 项目类别:
SUMO-BINDING MOTIFS MEDIATE THE RAD60-DEPENDENT RESPONSE
SUMO 结合基序调节 RAD60 依赖性反应
  • 批准号:
    7602145
  • 财政年份:
    2007
  • 资助金额:
    $ 68.78万
  • 项目类别:
NOVEL ESSENTIAL DNA REPAIR PROTEINS NSE1 AND NSE2 ARE SUBUNITS OF THE FISSION Y
新型必需 DNA 修复蛋白 NSE1 和 NSE2 是裂变 Y 的亚基
  • 批准号:
    7420711
  • 财政年份:
    2006
  • 资助金额:
    $ 68.78万
  • 项目类别:
NOVEL ESSENTIAL DNA REPAIR PROTEINS NSE1 AND NSE2 ARE SUBUNITS OF THE FISSION Y
新型必需 DNA 修复蛋白 NSE1 和 NSE2 是裂变 Y 的亚基
  • 批准号:
    7182424
  • 财政年份:
    2005
  • 资助金额:
    $ 68.78万
  • 项目类别:

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