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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

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