Co-Regulation of Alternative Lengthening of Telomeres and Chromatin Dynamics in ATRX-DAXX deficient cancer cells

ATRX-DAXX 缺陷癌细胞中端粒选择性延长和染色质动态的共同调节

• 批准号: 10652320
• 负责人: Roderick O'Sullivan
• 金额: $ 44.78万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-23 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652320
• 关键词: ADP ribosylation; ATRX gene; Acute; Adopted; Affect; Automobile Driving; Bypass; Cell Cycle; Cell division; Cells; Cessation of life; Chromatin; Chromatin Modeling; Chromatin Remodeling Factor; Chromosomes; Compensation; Complex; DAXX gene; DNA Damage; DNA Sequence Alteration; Data; Dedications; Deposition; Detection; Development; Disease; Disseminated Malignant Neoplasm; Enhancers; Ensure; Epigenetic Process; Event; Exhibits; G2 Phase; Genes; Genetic; Genetic Transcription; Genomic approach; Glioma; Histone H3.3; Maintenance; Malignant Neoplasms; Mediating; Mediator; Metabolic; Microscopy; Missense Mutation; Modeling; Molecular; Mutation; Names; Nucleosomes; Patients; Prognosis; Property; Proteins; Proteomics; Recurrence; Regulation; Reporting; Role; Running; Signal Transduction; Stress; Structure; Telomere Maintenance; Telomere Pathway; cancer cell; chromatin remodeling; cytotoxicity; epigenome; epithelial to mesenchymal transition; gain of function; genome integrity; genomic locus; histone modification; improved; innovation; loss of function mutation; prevent; promoter; public health relevance; reconstitution; recruit; repaired; response; targeted cancer therapy; telomere; therapeutic target; trait; tumor; tumorigenesis; ultra high resolution

Abstract Cancer cells must activate a telomere elongation mechanism and acquire genomic alterations. Many of the most lethal cancers rely on the Alternative Lengthening of Telomeres (ALT) pathway. ALT is a specialized homology directed repair (HDR) mechanism dedicated to repair and elongate telomeres, thereby ensuring the proliferative immortality of these cancer cells. Recurrent inactivating missense mutations in genes encoding the ATRX-DAXX chromatin remodeling/histone H3.3 deposition complex exhibit a strong concordance with tumors in which ALT is activated, with both arising late in metastatic disease. These loss of function mutations disrupt ATRX-DAXX mediated assembly of chromatin, provoking replicative stress and double-strand breaks (DSBs) within telomeres that is believed to stimulate ALT-associated HDR. Whereas the HDR mechanisms that underpin ALT have been extensively studied, the mechanisms governing how cells compensate for loss of ATRX-DAXX to maintain chromatin while also acquiring metastatic traits remain ill-defined. This proposal builds on our recent report that upon inactivation of ATRX-DAXX, a related chromatin assembly factor known as HIRA becomes indispensable for de novo histone H3.3 deposition and telomere extension in ALT cancer cells. Furthermore, we discovered that the depletion of HIRA provoked acute systemic death of ATRX-DAXX deficient cells. Strikingly, this cytotoxicity was reversed by reconstitution of ALT cells with wild type ATRX protein. These data provided compelling evidence for a compensatory function adopted by HIRA due to ATRX-DAXX deficiency that could be harnessed to eliminate ALT cancer cells.

抽象的 癌细胞必须激活端粒延长机制并获得基因组改变。许多最 致命的癌症依赖于端粒替代延长 (ALT) 途径。 ALT 是一种专门 同源定向修复（HDR）机制致力于修复和延长端粒，从而确保 这些癌细胞的增殖永生性。编码基因的反复失活错义突变 ATRX-DAXX 染色质重塑/组蛋白 H3.3 沉积复合物表现出强烈的一致性 ALT 被激活的肿瘤，两者均在转移性疾病晚期出现。这些功能丧失突变 破坏 ATRX-DAXX 介导的染色质组装，引发复制应激和双链断裂 端粒内的 DSB（DSB）被认为可以刺激 ALT 相关的 HDR。而 HDR 机制 ALT 的基础已被广泛研究，控制细胞如何补偿 ALT 损失的机制 ATRX-DAXX 在维持染色质的同时获得转移性状的作用仍不明确。这个提议 基于我们最近的报告，ATRX-DAXX 失活后，一种已知的相关染色质组装因子 因为 HIRA 对于 ALT 癌症中组蛋白 H3.3 的从头沉积和端粒延伸变得不可或缺 细胞。此外，我们发现 HIRA 的消耗会引起 ATRX-DAXX 的急性全身性死亡 缺乏细胞。引人注目的是，用野生型 ATRX 重建 ALT 细胞可逆转这种细胞毒性 蛋白质。这些数据为 HIRA 由于以下原因而采取的补偿功能提供了令人信服的证据： ATRX-DAXX 缺陷可用于消除 ALT 癌细胞。