Genome Integrity Through the Cell Cycle in Homeostasis and Cancer

稳态和癌症中细胞周期的基因组完整性

• 批准号: 10534250
• 负责人: Zachary Kenneth Mirman
• 金额: $ 9.64万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534250
• 关键词: Address; Antineoplastic Agents; Award; BRCA1 gene; Biochemistry; Biological; Biology; Cancer Biology; Cancer Etiology; Cancer Model; Cell Cycle; Cell division; Cell division phases; Cell physiology; Cells; Cellular biology; Choices and Control; Chromatin; Chromosomal Rearrangement; Chromosome Condensation; Chromosome Segregation; Chromosomes; Complex; Computer Analysis; Coupled; DNA; DNA Damage; DNA Primase; DNA Repair; DNA biosynthesis; Data; Data Set; Detection; Development; Disease; Double Strand Break Repair; Ensure; Excision; FDA approved; Gene Targeting; Genetic; Genetic Engineering; Genetic Transcription; Genome; Genome Stability; Genomic Instability; Goals; Heart; Homeostasis; Human; Immune system; In Vitro; Internet; Learning; Lesion; Licensing; Light; Maintenance; Malignant Neoplasms; Methods; Microscopy; Mitosis; Modeling; Molecular; Molecular Conformation; Mus; Mutation; Normal Cell; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Polymerase; Postdoctoral Fellow; Proteins; Proteolysis; Radiation therapy; Research; Research Project Grants; Resected; Resistance; Role; Sampling; Signal Transduction; Technical Expertise; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Topoisomerase; Topoisomerase Inhibitors; Tumor Suppression; Tumor Suppressor Proteins; Work; cancer cell; cancer therapy; cell growth regulation; cellular development; chemotherapy; clinically relevant; cytotoxicity; daughter cell; drug action; drug sensitivity; experience; genome integrity; genotoxicity; high throughput screening; homologous recombination; human data; improved; in vivo; in vivo Model; inhibitor; insight; mammalian genome; mouse model; mutant; novel; novel strategies; p53-binding protein 1; preservation; recruit; repaired; response; screening; segregation; shift work; stem cell biology; synergism; therapy outcome; tumor; tumorigenesis

Project Summary/Abstract The stability of the mammalian genome depends on a remarkable toolkit of surveillance, repair, signaling, and checkpoint mechanisms. Mutations in the DNA itself, or corruptions in many of these genome integrity mechanisms, can result in disease including cancer. Given the importance of mutation and cell division in tumorigenesis, two central pathways in genome integrity are the DNA damage response, and the cell division cycle. A more complete understanding of these pathways is crucial to our knowledge of normal cellular development in homeostasis, stem cell biology, the etiology of cancers, as well as for technical applications like gene targeting. This project seeks to tackle outstanding problems in these fields in order to elucidate fundamental molecular cell biology mechanisms that can improve therapeutic outcomes in cancer. The F99 phase is focused on double-strand break (DSB) repair and the control of end resection, a critical molecular ‘choice’ of whether to repair a DSB by blunt end-joining or by homologous recombination. I revealed novel mechanistic insights about the protein controlling this choice, 53BP1, findings relevant to the treatment of BRCA1-deficient cancers with PARP1 inhibitors. We found that—instead of blocking end resection as was generally thought—53BP1 recruits polymerase alpha to counteract resection by fill-in synthesis of the resected DSB. In the remainder of the dissertation work, I will explore how BRCA1 and 53BP1 regulate resection and fill-in synthesis in light of this new model. I will also gain the necessary experience and exposure scientifically and professionally to transition to a cancer-focused postdoc in a stellar lab. For the K00 phase, I will shift my focus and approaches to study mechanisms preserving genome integrity in the critical window of mitosis, where diverse chromatin biology pathways converge. I plan to learn and implement high throughput screens, computational analysis of larger, statistically-powerful data sets, as well as in vivo modeling in the mouse, and analysis of sequencing data from human tumor samples. These new approaches, coupled with my already strong background in genetics, microscopy, and biochemistry, will allow me to address the most pressing and challenging issues in genome integrity and cancer biology today. With the aid of this award, I intend to continue my research contribution and gain experience in order to become a leader of my own cancer-focused lab and a leader in the field of genome integrity.

项目概要/摘要 哺乳动物基因组的稳定性取决于出色的监视、修复、 信令和检查点机制。 DNA 本身的突变，或许多基因的损坏 这些基因组完整性机制可能导致包括癌症在内的疾病。鉴于 突变和细胞分裂在肿瘤发生中的重要性，这是基因组中的两个中心途径 完整性是DNA损伤反应和细胞分裂周期。更完整的 了解这些途径对于我们了解正常细胞发育至关重要 稳态、干细胞生物学、癌症病因学以及技术应用，例如 基因靶向。该项目旨在解决这些领域的突出问题，以便 阐明可以改善治疗的基本分子细胞生物学机制 癌症的结果。 F99阶段的重点是双链断裂（DSB）修复和末端控制 切除，是通过钝端连接还是通过钝端连接修复 DSB 的关键分子“选择” 同源重组。我揭示了有关蛋白质控制的新机制见解 这个选择，53BP1，与用 PARP1 治疗 BRCA1 缺陷型癌症相关的发现 抑制剂。我们发现——而不是像通常认为的那样阻碍末端切除——53BP1 招募聚合酶 α 通过填充合成切除的 DSB 来抵消切除。在 在论文的剩余部分，我将探讨 BRCA1 和 53BP1 如何调节切除和 根据这个新模型进行填充综合。我还将获得必要的经验和接触 以科学和专业的方式在一流的实验室中过渡到以癌症为重点的博士后。 对于K00阶段，我将把重点和方法转向研究保存机制 有丝分裂关键窗口中的基因组完整性，其中不同的染色质生物学途径 收敛。我计划学习并实现高通量筛选、计算分析 更大的、统计上强大的数据集，以及小鼠的体内建模，以及分析 来自人类肿瘤样本的测序数据。这些新方法，加上我已经 遗传学、显微镜学和生物化学方面的强大背景将使我能够解决最重要的问题 当今基因组完整性和癌症生物学中紧迫且具有挑战性的问题。借助 获得这个奖项后，我打算继续我的研究贡献并积累经验，以便 成为我自己的癌症实验室的领导者和基因组完整性领域的领导者。