Identification of a novel tumor suppressorof melanoma and UV-induced genome instability

黑色素瘤的新型肿瘤抑制因子和紫外线诱导的基因组不稳定性的鉴定

基本信息

  • 批准号:
    10539561
  • 负责人:
  • 金额:
    $ 19.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

Skin cancer is one of the most common cancers in the US and imposes a high economic burden. Most skin cancers, including malignant melanoma, are caused by ultraviolet (UV) light-induced DNA damage and genome instability. It is well known that UV radiation (UVR)-induced bulky DNA adducts are barriers for normal replication progression, and their formation causes replication fork stalling that is a major driving force of genome instability. Failure to stabilize stalled forks and resume stalled replication often causes fork collapse, generating DNA breaks and genome instabilities that lead to tumorigenesis. However, the mechanism underlying how genome stability is maintained and how stalled replication is rescued after UV exposure is poorly understood. Understanding such mechanism is thus important for understanding early events in melanomagenesis. Moreover, enhancing replication stress levels in tumor cells may offer a promising cancer therapeutic approach, in particular for treating cancers harboring mutations in replication stress response genes. Thus, obtaining an in-depth understanding on replication stress suppression and fork repair may assist in developing novel approaches to facilitate targeted therapy of melanoma. The long-term goal of our research program is to delineate the mechanisms for maintaining genome stability in response to exposure to environmental genotoxins. PI’s lab has pioneered in identifying the CST complex − a trimeric protein complex consisting of CTC1, STN1, TEN1 that binds to ssDNA with high affinity – as an important player in maintaining global genome integrity upon replication perturbation. Our recent data suggest the potential involvement of CST in suppressing UVR-induced genome instability. The goal of this proposal is to test the hypothesis that CST plays an important role in regulating replication reinitiation when forks are blocked by UV-induced bulky DNA adducts. CST dysfunction may elevate UVR-induced genome instability and increase melanoma formation. In Aim 1, we will determine how CST facilitates DNA synthesis when UV-induced bulky lesions block replication progression. In Aim 2, we will use a new mouse model to determine whether specific disruption of STN1 in mature melanocytes promotes UVR-induced melanoma production in vivo. It is expected that results from the proposed research will offer novel insights into our understanding of genome protection after UV damage and potentially identify a novel tumor suppressor of melanoma, thus facilitating the development of new approaches for melanoma therapy.
皮肤癌是美国最常见的癌症之一,造成了很高的经济负担。大多数皮肤

项目成果

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Weihang Chai其他文献

Weihang Chai的其他文献

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{{ truncateString('Weihang Chai', 18)}}的其他基金

Molecular Basis of Coats Plus Disease
Coats Plus 疾病的分子基础
  • 批准号:
    10607126
  • 财政年份:
    2023
  • 资助金额:
    $ 19.25万
  • 项目类别:
Molecular Basis of Coats Plus Disease
Coats Plus 疾病的分子基础
  • 批准号:
    10797782
  • 财政年份:
    2023
  • 资助金额:
    $ 19.25万
  • 项目类别:
Role of Telomerase is DSB Repair
端粒酶的作用是 DSB 修复
  • 批准号:
    10052953
  • 财政年份:
    2019
  • 资助金额:
    $ 19.25万
  • 项目类别:
Molecular Modulator of RPA and RAD51 in Maintaining Genome Stability
RPA 和 RAD51 维持基因组稳定性的分子调节剂
  • 批准号:
    10153729
  • 财政年份:
    2019
  • 资助金额:
    $ 19.25万
  • 项目类别:
Molecular Modulator of RPA and RAD51 in Maintaining Genome Stability
RPA 和 RAD51 维持基因组稳定性的分子调节剂
  • 批准号:
    10055860
  • 财政年份:
    2019
  • 资助金额:
    $ 19.25万
  • 项目类别:
Molecular Modulator of RPA and RAD51 in Maintaining Genome Stability
RPA 和 RAD51 维持基因组稳定性的分子调节剂
  • 批准号:
    10322742
  • 财政年份:
    2019
  • 资助金额:
    $ 19.25万
  • 项目类别:
Molecular Modulator of RPA and RAD51 in Maintaining Genome Stability
RPA 和 RAD51 维持基因组稳定性的分子调节剂
  • 批准号:
    10541201
  • 财政年份:
    2019
  • 资助金额:
    $ 19.25万
  • 项目类别:
Role of human CST in preventing telomere loss
人类 CST 在预防端粒丢失中的作用
  • 批准号:
    9145437
  • 财政年份:
    2015
  • 资助金额:
    $ 19.25万
  • 项目类别:
Mechanisms of fork restart in response to genotoxic stress
响应基因毒性应激的分叉重启机制
  • 批准号:
    8800247
  • 财政年份:
    2014
  • 资助金额:
    $ 19.25万
  • 项目类别:
Mechanisms of fork restart in response to genotoxic stress
响应基因毒性应激的分叉重启机制
  • 批准号:
    9551636
  • 财政年份:
    2014
  • 资助金额:
    $ 19.25万
  • 项目类别:

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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
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