Deciphering the role of heterochromatin in telomere function and maintenance mechanisms

破译异染色质在端粒功能和维持机制中的作用

• 批准号: 10809508
• 负责人: Nausica C. Arnoult
• 金额: $ 1.05万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10809508
• 关键词: ATRX gene; Buffers; Cancerous; Cell Aging; Cell Cycle Arrest; Cells; Chromatin; Chromosomes; Code; DAXX gene; DNA; DNA Damage; DNA Repair Gene; Deposition; Development; Enzymes; Event; Genetic Recombination; Genome Stability; Heterochromatin; Maintenance; Malignant Neoplasms; Methylation; Mitotic; Nucleoproteins; Nucleosomes; Pathway interactions; Role; Signal Transduction; Structure; Telomerase; Telomere Maintenance; Telomere Recombination; cancer cell; density; prevent; repaired; senescence; telomere; tumor

PROJECT SUMMARY Telomeres are nucleoprotein structures that protect the ends of linear chromosomes and thereby maintain genome stability. Telomeres solve both the end-protection and the end-replication problems: 1) They inhibit DNA damage at chromosome ends, which would otherwise resemble broken DNA, 2) Since chromosome ends shorten during replication, telomeres act as buffer sequences to prevent loss of coding regions, 3) Once telomeres become too short, they can no longer inhibit DNA damage, leading to permanent cell cycle arrest (senescence). This “mitotic clock” is a critical tumor-suppressive barrier that forces aging cells to stop dividing. To become cancerous, cells must acquire unlimited division potential by activating a telomere maintenance mechanism, either reactivation of telomerase, the enzyme that elongates telomeres during development, or through the alternative lengthening of telomeres (ALT) mechanism, which is based on recombination. ALT+ cancers cells are characterized by clustering of telomeres into ALT-associated PML bodies (APBs) that serve as platforms for telomere recombination. ALT+ telomeres also display singular chromatin, with a lower nucleosome density and loss of the ATRX/DAXX pathway that normally deposits H3.3 at telomeres. We found, however, that H3K9 trimethylation at telomeres promotes formation of APBs, as well as subsequent ALT activity. We propose here to determine which chromatin regulators as well as DNA damage and repair genes modulate APB formation in ALT+ cells.

项目摘要 端粒是核蛋白结构，其保护线性染色体的末端， 保持基因组的稳定性。端粒解决了末端保护和末端复制问题：1） 它们抑制染色体末端的DNA损伤，否则这将类似于断裂的DNA，2）由于 染色体末端在复制过程中缩短，端粒作为缓冲序列防止编码丢失 3）一旦端粒变得太短，它们就不能再抑制DNA损伤，导致 永久性细胞周期停滞（衰老）。这种“有丝分裂钟”是一种重要的肿瘤抑制屏障， 迫使老化细胞停止分裂要变成癌细胞必须获得无限的分裂潜能 通过激活端粒维持机制，或者重新激活端粒酶， 在发育过程中延长端粒，或通过端粒的替代性延长（ALT） 机制，这是基于重组。 ALT+癌细胞的特征是端粒聚集成ALT相关的PML小体（APB） 作为端粒重组的平台。ALT+端粒也显示单一的染色质， 较低的核小体密度和ATRX/DAXX途径的损失，该途径通常在 端粒然而，我们发现，端粒上的H3 K9三甲基化促进了APB的形成， 以及随后的ALT活性。我们建议在这里，以确定哪些染色质调节以及 因为DNA损伤和修复基因调节ALT+细胞中APB的形成。