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：
Weihang Chai
金额：
$ 19.25万
依托单位：
LOYOLA UNIVERSITY CHICAGO
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

来源：
https://reporter.nih.gov/project-details/10539561
关键词：
Affect Affinity Binding Binding Proteins Bypass CRISPR/Cas technology Cells Collaborations Complex DNA DNA Adducts DNA Damage DNA Sequence Alteration DNA biosynthesis DNA lesion DNA replication fork Data Development Economic Burden Event Exposure to Failure Functional disorder Genes Genome Genome Stability Genomic Instability Goals Human Knowledge Lead Lesion Malignant Neoplasms Mediating Modeling Molecular Mutagens Mutation Nature Pathology Pathway interactions Play Production Public Health Research Research Personnel Role Sampling Skin Skin Cancer Telomere Maintenance Testing The Cancer Genome Atlas Therapeutic Tumor Suppressor Proteins UV Radiation Exposure UV induced UV-induced melanoma Ultraviolet Rays biological adaptation to stress cell injury cell transformation conditional knockout driving force genome integrity in vivo innovation insight melanocyte melanoma melanomagenesis mouse model neoplastic cell novel novel strategies prevent programs protein complex repaired replication stress response skin organogenesis targeted treatment tumor tumorigenesis ultraviolet damage ultraviolet lesions

Affect Affinity Binding Binding Proteins Bypass CRISPR/Cas technology Cells Collaborations Complex DNA DNA Adducts DNA Damage DNA Sequence Alteration DNA biosynthesis DNA lesion DNA replication fork Data Development Economic Burden Event Exposure to Failure Functional disorder Genes Genome Genome Stability Genomic Instability Goals Human Knowledge Lead Lesion Malignant Neoplasms Mediating Modeling Molecular Mutagens Mutation Nature Pathology Pathway interactions Play Production Public Health Research Research Personnel Role Sampling Skin Skin Cancer Telomere Maintenance Testing The Cancer Genome Atlas Therapeutic Tumor Suppressor Proteins UV Radiation Exposure UV induced UV-induced melanoma Ultraviolet Rays biological adaptation to stress cell injury cell transformation conditional knockout driving force genome integrity in vivo innovation insight melanocyte melanoma melanomagenesis mouse model neoplastic cell novel novel strategies prevent programs protein complex repaired replication stress response skin organogenesis targeted treatment tumor tumorigenesis ultraviolet damage ultraviolet lesions

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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，不可能带来巨大的经济负担。大多数皮肤包括恶性黑色素瘤在内的癌症是由紫外线（UV）光诱导的DNA损伤和基因组引起的不稳定。众所周知，紫外线辐射（UVR）诱导的大量DNA加合物是正常复制的障碍进展及其形成会导致复制叉的停滞，这是基因组不稳定性的主要驱动力。无法稳定失速的叉子和恢复停滞的复制通常会导致叉子崩溃，从而产生DNA断裂以及导致肿瘤发生的基因组不稳定性。但是，基因组稳定性的基础机制在紫外线暴露不足之后，维持以及如何恢复停滞的复制。理解这样因此，机制对于理解黑素作发生的早期事件很重要。而且，增强肿瘤细胞中的复制应力水平可能提供有希望的癌症治疗方法，特别是用于治疗复制应力反应基因中有突变的癌症。那，对复制应力抑制和分叉维修可能有助于开发新的方法以促进目标黑色素瘤的治疗。我们研究计划的长期目标是描述维持基因组稳定的机制 PI的实验室已经率先确定CST复合物 - 由CTC1，STN1，TEN1组成的三聚蛋白复合物与具有高亲和力的ssDNA结合 - 在复制扰动时保持全球基因组完整性的重要参与者。我们最近的数据暗示 CST在抑制UVR诱导的基因组不稳定性中的潜在参与。该提议的目的是测试CST在调节叉子时重新定制复制中起重要作用的假设通过紫外线诱导的笨重的DNA加合物。 CST功能障碍可能会提高UVR诱导的基因组不稳定性并增加黑色素瘤形成。在AIM 1中，我们将确定紫外线诱导的笨重时CST收藏夹如何合成DNA合成病变阻止复制进展。在AIM 2中，我们将使用新的鼠标模型来确定是否具体成熟的黑色素细胞中STN1的破坏会促进体内UVR诱导的黑色素瘤产生。预计拟议研究的结果将为我们对我们对基因组保护的理解提供新颖的见解紫外线损伤并有可能识别出新型的黑色素瘤肿瘤抑制剂，从而促进开发黑色素瘤疗法的新方法。