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

皮肤癌是美国最常见的癌症之一，并造成很高的经济负担。大多数皮肤 包括恶性黑色素瘤在内的癌症是由紫外线（UV）诱导的DNA损伤和基因组损伤引起的。 不稳定众所周知，紫外线辐射（UVR）诱导的大体积DNA加合物是正常复制的障碍 它们的形成导致复制叉停滞，这是基因组不稳定性的主要驱动力。 如果不能稳定停滞的分叉和恢复停滞的复制，通常会导致分叉崩溃，产生DNA断裂 和基因组不稳定性导致肿瘤发生。然而，基因组稳定性的机制 以及在紫外线照射后如何挽救停滞的复制，人们知之甚少。理解这些 因此，机制对于理解黑色素瘤发生的早期事件是重要的。此外，加强 肿瘤细胞中的复制应激水平可以提供有希望的癌症治疗方法，特别是用于治疗 携带复制应激反应基因突变的癌症。因此，深入了解 复制应激抑制和叉修复可能有助于开发新的方法，以促进靶向 黑色素瘤的治疗 我们研究计划的长期目标是阐明维持基因组稳定性的机制 暴露于环境遗传毒素的反应。PI的实验室率先识别了CST复合物- 由CTC 1、STN 1、TEN 1组成的三聚体蛋白复合物，其以高亲和力结合ssDNA-作为 在复制扰动后维持全球基因组完整性的重要参与者。我们最近的数据显示 CST可能参与抑制紫外线诱导的基因组不稳定性。本提案的目的是 检验当分叉被阻断时，CST在调节复制重新启动中起重要作用的假设 紫外线诱导的大体积DNA加合物。CST功能障碍可能会增加UVR诱导的基因组不稳定性， 黑素瘤形成。在目标1中，我们将确定当UV诱导的大体积DNA合成时，CST如何促进DNA合成。 病变阻断复制进展。在目标2中，我们将使用一种新的小鼠模型来确定是否特异性地 成熟黑素细胞中STN 1的破坏促进体内UV诱导的黑色素瘤产生。预计 这项研究的结果将为我们理解基因组保护提供新的见解 紫外线损伤后，并可能确定一种新的肿瘤抑制黑色素瘤，从而促进 黑色素瘤治疗新方法的开发。

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.