Roles of nuclear architecture and phase separation in heterochromatin repair dynamics

核结构和相分离在异染色质修复动力学中的作用

• 批准号: 10390198
• 负责人: Irene E Chiolo
• 金额: $ 21万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390198
• 关键词: Actins; Affect; Aging; Architecture; Biochemical; Cancer Etiology; Cells; Chromatin; Chromosomes; Complex; Country; DNA Repair; DNA Sequence; DNA biosynthesis; Data; Detection; Development; Disease; Double Strand Break Repair; Drosophila genus; Early Diagnosis; Exposure to; F-Actin; Failure; Foundations; Genes; Genetic Recombination; Genome; Genome Stability; Genomic Instability; Goals; Health; Heterochromatin; Human; Human Genome; Investments; Ionizing radiation; Knowledge; Link; Longevity; Malignant Neoplasms; Microfilaments; Modeling; Molecular; Movement; Mutation; Myosin ATPase; Normal Cell; Nuclear; Nuclear Pore Complex Proteins; Organism; Outcomes Research; Pathway interactions; Phase; Prevention; Process; Publishing; Regulation; Resolution; Risk; Role; Screening for cancer; Sister Chromatid; Site; Source; Structure; Sumoylation Pathway; Testing; Therapeutic Intervention; Time; base; biophysical properties; cancer cell; cancer prevention; cancer therapy; cancer type; driving force; genome integrity; genome-wide; homologous recombination; human disease; imaging genetics; improved; prevent; recombinational repair; repaired; response; tumor progression; tumorigenesis; ubiquitin-protein ligase

SUMMARY Advancing our knowledge of pericentromeric heterochromatin repair is a high impact investment for improving human health: heterochromatin is a poorly characterized region comprising nearly a third of the human genome; double-strand break (DSB) repair failures in this region affect not just specific genes, but also genome-wide stability; and the likelihood of failures is high because of the many repeated sequences that characterize this domain. Despite the foundational importance of characterizing these processes, DSB repair mechanisms in heterochromatin are largely understudied. We discovered a specialized pathway that promotes faithful homologous recombination (HR) repair in heterochromatin while preventing aberrant recombination, effectively isolating heterochromatic repair sites to the nuclear periphery before strand invasion. We have recently identified several components required for this process, including nuclear actin filaments (F-actin) and myosins, and chromatin-associated nucleoporins, but the regulation and function of these components remain poorly understood. Dysregulation of heterochromatin repair is likely one of the most underestimated and powerful sources of tumorigenesis, and identifying the components involved is essential for understanding cancer etiology and developing more effective strategies for therapeutic intervention. Our central hypothesis is that F-actin, myosins, nucleoplasmic nucleoporins, and phase separation are essential regulators of heterochromatin repair dynamics, and that SUMOylation participates in coordinating their function in repair progression. We will combine a wealth of super resolution imaging, genetic and biochemical approaches to investigate the molecular mechanisms involved in these processes. Expected positive outcomes of this research include the systematic identification of the molecular machinery that protects heterochromatin from massive genome rearrangements, enabling successful completion of HR repair. These studies are also expected to illuminate missing links between nuclear architecture and dynamics, phase separation, repair progression, and the stability of repeated DNA sequences. These results will have an important positive impact by identifying crucial safeguard mechanisms used by normal cells to protect the genome from environmental threats. Mutations in these pathways result in genome instability, tumorigenesis, and reduced life span. Thus, we expect that the proposed studies and future research will trigger exciting advancements in the prevention, early detection, and treatment of cancer and other human diseases associated with genome instability and aging-related disorders.

概括 促进我们对周围质聚染色质修复的了解是改善的高影响投资 人类健康：异染色质是一个较差的区域，占人类的近三分之一 基因组；该区域的双链断裂（DSB）维修故障不仅影响特定基因，还会影响 全基因组稳定性；失败的可能性很高，因为许多重复的序列 表征此域。尽管表征这些过程的基本重要性，但DSB维修 异染色质中的机制在很大程度上被研究了。我们发现了一条促进的专业途径 忠实的同源重组（HR）修复异染色质，同时预防异常重组， 在链入侵之前，有效地将异质修复位点分离为核外围。我们有 最近确定了此过程所需的几个组件，包括核肌动蛋白丝（F-肌动蛋白）和 肌球蛋白和染色质相关的核苷，但这些成分的调节和功能仍然存在 理解不佳。异染色质修复失调可能是最被低估的，并且 肿瘤发生的强大来源，并确定所涉及的组件对于理解至关重要 癌症病因和制定更有效的治疗干预策略。我们的中心假设是 那个F-肌动蛋白，肌动物，核质核苷和相分离是必不可少的调节剂 异染色质修复动力学，该sumoylation参与协调其在修复中的功能 进展。我们将结合大量的超级分辨率成像，遗传和生化方法 研究这些过程中涉及的分子机制。预期的积极结果 研究包括对保护异染色质免受的分子机械的系统鉴定 大规模的基因组重排，可以成功完成人力资源修复。这些研究也是 预计会照亮核架构与动态，相位，维修之间缺失的联系 进展以及重复的DNA序列的稳定性。这些结果将产生重要的积极影响 通过识别正常细胞用来保护基因组免受环境的关键保障机制 威胁。这些途径中的突变导致基因组不稳定性，肿瘤发生和寿命降低。因此， 我们预计拟议的研究和未来的研究将引发预防的令人兴奋的进步， 早期发现和治疗与基因组不稳定性相关的癌症和其他人类疾病 与衰老有关的疾病。