The mechanism of DNA damage and chromothripsis from chromosome segregation errors

染色体分离错误导致 DNA 损伤和染色体碎裂的机制

• 批准号: 9306800
• 负责人: Alexander Spektor
• 金额: $ 17.71万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306800
• 关键词: Advisory Committees; Affect; Antimitotic Agents; Area; Award; Birth; Cell Cycle; Cell Death; Cell Nucleus; Cell division; Cells; Cellular biology; Chromosome Segregation; Chromosomes; Clone Cells; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Damage; DNA Fragmentation; DNA Repair; DNA biosynthesis; DNA copy number; Data; Derivative Chromosome; Development; Dose; Double Minutes; Drug Targeting; Drug resistance; Environment; Event; Evolution; Exhibits; Frequencies; Future; G1 Phase; Generations; Genetic; Genetic Transcription; Genome; Genomic Instability; Genomics; Goals; Image; International; Interphase; Laboratories; Lead; Ligation; Malignant Neoplasms; Mediating; Mentors; Methods; Microtubule Stabilization; Mitosis; Mitotic; Mutagenesis; Mutation; Nonhomologous DNA End Joining; Nuclear; Nuclear Envelope; Nuclear Structure; Oncogenes; Outcome; Paclitaxel; Pattern; Physicians; Positioning Attribute; Procedures; Process; Radiation; Radiation Oncology; Replication Error; Research; Research Personnel; Research Proposals; Rupture; S Phase; Scientist; Shapes; Side; Spontaneous Rupture; Stress; Structure; System; Techniques; Testing; Tissues; Training; Universities; base; cancer cell; cancer genome; cancer therapy; career; career development; cell killing; chemotherapeutic agent; chromothripsis; clinical development; clinically relevant; daughter cell; design; experimental study; genome sequencing; innovation; killings; live cell imaging; novel therapeutics; nuclease; programs; taxane; tenure track; therapy resistant; tumor; tumorigenesis; whole genome

Project Summary/Abstract Research: Tumorigenesis and resistance to therapy are generally believed to arise through gradual, multigenerational accrual of mutations. However, recent cancer genome sequencing suggests that many cancers may accumulate large number of mutations rapidly, perhaps during the course of a single cell cycle. The most dramatic example of such rapid genome evolution is chromothripsis, a new mutational process with massive chromosome rearrangements and a unique pattern DNA copy number that is curiously restricted to one or a few chromosomes. The mechanism(s) leading to chromothripsis have been unclear, but our group previously suggested that it could result from the physical isolation of chromosomes in abnormal nuclear structures called micronuclei. To test this hypothesis, I developed a procedure to combine live- cell imaging with single-cell whole genome sequencing. This has enabled me, with my collaborators, to recapitulate chromothripsis in the laboratory and demonstrate that it can occur via chromosome fragmentation in micronuclei. This experimental system now positions me to study the mechanism of chromothripsis in detail. I will also test my hypotheses that chromothripsis triggers a downstream cascade of genome instability and drives tumor formation through generation of double minute chromosomes, and that chromothriptic-like DNA damage may be an important facet of the tumor killing action of taxanes. Together, these experiments and the new hypotheses being tested will advance our understanding of the ways by which chromosome segregation errors shape cancer genomes, leading to development of novel therapeutic strategies. Candidate Career Goals: My long-term career objective is to obtain a tenure-track position as a physician-scientist in a radiation oncology department. The K08 award will provide the advanced training necessary to achieve this goal. This research proposal is part of a structured plan with scientific, technical, clinical, and career development components. Environment: DFCI and Harvard University are internationally recognized research programs with a number of expert researchers in the areas of cancer cell biology and genomics. Furthermore, DFCI Department of Radiation Oncology has a distinguished record of training successful physician-scientists. In order to achieve my goals, I will be mentored by two outstanding scientists, Dr. David Pellman and Dr. Matthew Meyerson. I have also assembled an excellent advisory committee, consisting of Dr. Alan D’Andrea, Dr. Tim Mitchison, Dr. Gad Getz and Dr. Harvey Mamon.

项目总结/摘要 研究：肿瘤发生和对治疗的抵抗通常被认为是通过以下方式产生的： 逐渐的，多代累积的突变。然而，最近的癌症基因组测序 这表明许多癌症可能会迅速积累大量的突变，也许在 一个细胞周期的过程。这种快速基因组进化的最引人注目的例子是 chromothripsis，一个新的突变过程，大量的染色体重排和 一种独特的DNA拷贝数模式，奇怪的是仅限于一条或几条染色体。 导致染色体断裂的机制尚不清楚，但我们的小组以前 这可能是由于异常核内染色体的物理分离所致 称为微核。为了验证这个假设，我开发了一个程序来结合联合收割机- 单细胞全基因组测序的细胞成像。这使我能够与我的 合作者，在实验室中概括chromothripsis，并证明它可以发生， 通过微核中的染色体断裂。 这个实验系统现在让我研究了 详细我还将测试我的假设，即chromothripsis触发下游级联反应， 基因组的不稳定性，并通过产生双微 染色体，而嗜色性样DNA损伤可能是一个重要方面， 紫杉烷类的肿瘤杀伤作用。总之，这些实验和新的假设 测试将推进我们对染色体分离错误的方式的理解 塑造癌症基因组，导致新的治疗策略的发展。 候选人职业目标：我的长期职业目标是获得一个终身职位， 一个放射肿瘤科的医生兼科学家。K 08奖将提供 为实现这一目标，必须进行先进的培训。该研究计划是一个结构化的 科学，技术，临床和职业发展组成部分的计划。 环境：DFCI和哈佛大学是国际公认的研究项目 与癌症细胞生物学和基因组学领域的许多专家研究人员合作。 此外，DFCI放射肿瘤科有着出色的培训记录 成功的物理学家为了实现我的目标，我将由两个 杰出的科学家大卫佩尔曼博士和马修迈耶森博士我还收集了一个 优秀的咨询委员会，由Alan D 'Andrea博士，Tim Mitchison博士，Gad Getz博士组成 和哈维·马蒙医生