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: 10523138
• 负责人: Zachary Kenneth Mirman
• 金额: $ 9.33万
• 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/10523138
• 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; 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; Instruction; Internet; Learning; Lesion; 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; Radio; Research; Research Project Grants; Resected; Resistance; Role; Sampling; Signal Transduction; Technical Expertise; Techniques; Technology; Testing; Therapeutic Intervention; Topoisomerase; Tumor Suppression; Tumor Suppressor Proteins; Work; base; cancer cell; cancer therapy; cell growth regulation; cellular development; clinically relevant; cytotoxicity; daughter cell; 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.

项目总结/摘要 哺乳动物基因组的稳定性依赖于一套出色的监测、修复、 信号和检查点机制。DNA本身的突变，或许多 这些基因组完整性机制可导致包括癌症在内的疾病。鉴于 基因组中突变和细胞分裂两条中心通路在肿瘤发生中重要性 完整性是DNA损伤反应和细胞分裂周期。更完整 了解这些途径对我们了解正常细胞发育至关重要， 稳态，干细胞生物学，癌症的病因学，以及技术应用， 基因靶向该项目旨在解决这些领域的突出问题， 阐明可以改善治疗效果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 切除术是一种关键的分子“选择”，即是通过钝端连接还是通过 同源重组我揭示了关于蛋白质控制的新的机制见解， 这个选择，53 BP 1，与用PARP 1治疗BRCA 1缺陷型癌症相关的发现， 抑制剂的我们发现，53 BP 1不是像通常认为的那样阻塞末端切除， 募集聚合酶α以通过切除的DSB的填充合成来抵消切除。在 在论文的其余部分，我将探讨BRCA 1和53 BP 1如何调节切除， 根据这种新模式进行填充合成。我也将获得必要的经验和曝光 科学和专业地过渡到一个恒星实验室的癌症研究博士后。 对于K 00阶段，我将把我的重点和方法转移到研究保留机制上 在有丝分裂的关键窗口中的基因组完整性， 收敛我计划学习和实施高通量筛选，计算分析， 更大的，强大的数据集，以及在小鼠体内建模，和分析 来自人类肿瘤样品的测序数据。这些新的方法，加上我已经 在遗传学，显微镜和生物化学的强大背景，将使我能够解决最 当今基因组完整性和癌症生物学中的紧迫和挑战性问题。的帮助下 这个奖项，我打算继续我的研究贡献，并获得经验，以 成为我自己的癌症实验室的领导者，也成为基因组完整性领域的领导者。