Defining the molecular basis of oncogene-induced replication stress

定义癌基因诱导的复制应激的分子基础

• 批准号: 10515661
• 负责人: Tony Tung Huang
• 金额: $ 43.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515661
• 关键词: Acceleration; Address; Affect; Biological; CCNE1 gene; Cancer cell line; Carcinogens; Cell physiology; Cells; Characteristics; Chromosome Breakage; Codon Nucleotides; DNA; DNA Damage; DNA biosynthesis; DNA replication fork; DNA-Directed DNA Polymerase; Deceleration; Development; Ensure; Environment; Event; Future; Gene Amplification; Genes; Genetic Transcription; Genome; Genomic Instability; Genomics; Goals; Head; Human; In Vitro; Investigation; Knowledge; Malignant Neoplasms; Modeling; Molecular; Mutagens; Nucleotides; Oncogene Activation; Oncogenes; Oncogenic; Ovarian Serous Adenocarcinoma; Pathway interactions; Physiological; Play; Point Mutation; Poly A; Polyadenylation; Premalignant Cell; Probability; Process; Proto-Oncogenes; RNA Polymerase II; Regulation; Replication Initiation; Reporting; Research; Role; Shapes; Site; Source; Speed; Techniques; Testing; Time; Transcription Initiation Site; Translating; Tumor Suppressor Genes; biological adaptation to stress; cancer therapy; carcinogenesis; deprivation; genome integrity; genome-wide; genotoxicity; in vitro Model; innovation; nucleotide metabolism; overexpression; premalignant; prevent; programs; recruit; replication stress; response; restraint; tumorigenesis

PROJECT SUMMARY/ABSTRACT Environmental genotoxic carcinogens target numerous proto-oncogenes (and tumor-suppressor genes) to induce point mutations in key codons, leading to oncogene activation. Oncogene activation disturbs a wide range of cellular processes, including alterations in the genomic and molecular landscape of precancerous cells that contributes to genomic instability, which accelerates chromosomal breakages, rearrangements and promotes tumorigenesis. Part of this cellular turmoil involves early deregulation of physiologic DNA replication, known as replication stress. Oncogene-induced replication stress is an early driver of genomic instability and is attributed to a plethora of factors, most notably aberrant origin firing, replication-transcription collisions, and defective nucleotide metabolism. Despite much progress in the field, the mechanisms through which oncogenes induce replication stress, particularly in early events leading to carcinogenesis, remains poorly understood. Major gaps in our knowledge of this process include: 1) What are the early steps that contributes to oncogene-induced replication stress in precancerous cells? and 2) How are replication stress response factors coordinated to overcome/resolve replication stress in a time-dependent manner? Research into these questions have been hampered by limitations inherent in using traditional cancer cell lines and cell biological approaches that may or may not accurately reflect the temporal and spatial regulation of the DNA replication stress response in a more physiologically-relevant in vitro pre-cancer model. In this application, we propose to address these knowledge gaps by using cancer-relevant primary human cells to explore how oncogene-induced replication stress can shape genome-wide replication fork initiation and termination sites, focusing on how these changes in the replication program will impact genome integrity. Furthermore, we will determine how recently discovered players in the replication stress response pathway are regulated to subvert oncogene-induced replication stress. Deciphering the mechanisms that contribute to this early replication stress response at the genome-wide level may provide new avenues for targeted cancer treatment. The questions we address here will set the stage for future investigations that include (but are not limited to) analyses of how environmental genotoxins may influence oncogene-induced replication stress to exacerbate genomic instability to accelerate tumorigenesis.

项目概要/摘要 环境基因毒性致癌物以多种原癌基因（和肿瘤抑制基因）为目标 诱导关键密码子点突变，导致癌基因激活。癌基因激活干扰范围广泛 细胞过程的变化，包括癌前细胞基因组和分子景观的改变 导致基因组不稳定，加速染色体断裂、重排并促进 肿瘤发生。这种细胞混乱的一部分涉及生理 DNA 复制的早期失调，称为 复制压力。癌基因诱导的复制应激是基因组不稳定的早期驱动因素，归因于 多种因素造成，最显着的是异常的起源激发、复制-转录冲突和缺陷 核苷酸代谢。尽管该领域取得了很大进展，但癌基因诱导的机制 复制应激，特别是在导致致癌的早期事件中，人们仍然知之甚少。主要差距 据我们所知，这一过程包括： 1) 导致癌基因诱导的早期步骤是什么？ 癌前细胞的复制应激？ 2）复制应激反应因素如何协调 以时间依赖的方式克服/解决复制压力？对这些问题的研究 受到使用传统癌细胞系和细胞生物学方法固有的局限性的阻碍，这些局限性可能或 可能无法准确地反映 DNA 复制应激反应的时空调节。 生理相关的体外癌前模型。 在此应用中，我们建议通过使用与癌症相关的原代人类来解决这些知识差距 细胞探索癌基因诱导的复制应激如何影响全基因组复制叉的启动和 终止位点，重点关注复制程序中的这些变化将如何影响基因组完整性。 此外，我们将确定最近发现的复制应激反应途径中的参与者是如何 调节以破坏癌基因诱导的复制应激。破译促成这一现象的机制 全基因组水平的早期复制应激反应可能为靶向癌症提供新途径 治疗。我们在此提出的问题将为未来的调查奠定基础，其中包括（但不包括） 仅限于）分析环境基因毒素如何影响癌基因诱导的复制应激 加剧基因组不稳定性，加速肿瘤发生。