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.

项目总结/摘要 环境遗传毒性致癌物靶向许多原癌基因（和肿瘤抑制基因）， 在关键密码子中诱导点突变，导致癌基因激活。癌基因激活干扰了广泛的 包括癌前细胞的基因组和分子景观的改变， 有助于基因组的不稳定性，加速染色体断裂，重排和促进 肿瘤发生这种细胞混乱的一部分涉及早期生理DNA复制的失调，称为 复制应力癌基因诱导的复制应激是基因组不稳定性的早期驱动因素， 与过多的因素有关，最明显的是异常的起源放电，复制-转录碰撞和缺陷 核苷酸代谢尽管在该领域取得了很大进展，但癌基因诱导肿瘤细胞凋亡的机制仍不清楚。 复制应激，特别是在导致癌变的早期事件中，仍然知之甚少。重大差距 我们对这一过程的了解包括：1）哪些早期步骤有助于癌基因诱导的 癌前细胞中的复制应激以及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？对这些问题的研究已经 由于使用传统的癌细胞系和细胞生物学方法中固有的局限性， 可能不能准确反映DNA复制应激反应的时间和空间调节， 生理学相关的体外癌前模型。 在本申请中，我们建议通过使用癌症相关的初级人类， 细胞来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， 终止位点，重点是如何在复制程序中的这些变化将影响基因组的完整性。 此外，我们将确定如何最近发现的球员在复制应激反应途径是 调节以破坏癌基因诱导的复制应激。解读导致这一现象的机制 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的途径 治疗我们在这里提出的问题将为未来的调查奠定基础，这些调查包括（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以加速肿瘤发生。