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，造成很高的经济负担。大多数皮肤 癌症，包括恶性黑色素瘤，是由紫外线(UV)光引起的DNA损伤和基因组引起的 不稳定。众所周知，紫外线辐射(UVR)诱导的大体积DNA加合物是正常复制的障碍 它们的形成导致复制分叉停滞，这是基因组不稳定的主要推动力。 未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，从而导致DNA断裂 以及导致肿瘤发生的基因组不稳定性。然而，基因组稳定性背后的机制是 以及在紫外线暴露后如何挽救停滞不前的复制，人们对此知之甚少。了解以下内容 因此，机制对于理解黑色素瘤发生的早期事件很重要。此外，加强 肿瘤细胞的复制应激水平可能提供一种很有前途的癌症治疗方法，特别是在治疗 具有复制应激反应基因突变的癌症。从而，深入了解 复制应激抑制和分叉修复可能有助于开发新的方法来促进有针对性的 黑色素瘤的治疗。 我们研究计划的长期目标是描绘维持基因组稳定的机制。 以应对环境中的基因毒素。Pi的实验室率先发现了cst复合体− 一种三聚体蛋白质复合体，由CTC1、STN1、TEN1与单链DNA高亲和力结合而成 在复制扰动下维持全球基因组完整性的重要角色。我们最近的数据表明 CST在抑制UVR诱导的基因组不稳定性中的潜在作用。这项提议的目标是 测试假设，当分叉被阻塞时，CST在调节复制重新启动中起重要作用 通过紫外线诱导的大体积DNA加合物。CST功能障碍可能增加UVR诱导的基因组不稳定性和增加 黑色素瘤的形成。在目标1中，我们将确定当紫外线诱导体积增大时，CST如何促进DNA合成 病变阻碍复制进程。在目标2中，我们将使用一种新的小鼠模型来确定特定的 破坏成熟黑素细胞中的STN1促进体内UVR诱导的黑色素瘤的产生。这是意料之中的 这项拟议研究的结果将为我们理解基因组保护提供新的见解 在紫外线损伤后，并有可能确定一种新的黑色素瘤肿瘤抑制因子，从而促进 黑色素瘤治疗新方法的发展。

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.