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: 10440845
• 负责人: Roderick O'Sullivan
• 金额: $ 45.7万
• 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/10440845
• 关键词: ADP ribosylation; ATRX gene; Acute; Address; Adopted; Affect; Attenuated; Automobile Driving; Bypass; Cell Cycle; Cell division; Cells; Cessation of life; Chromatin; Chromatin Modeling; Chromatin Remodeling Factor; Chromosomes; Complex; DAXX gene; DNA; DNA Damage; DNA Sequence Alteration; Data; Deposition; Detection; Development; Disease; Enhancers; Ensure; Epigenetic Process; Event; Exhibits; G2 Phase; Genes; Genetic; Genetic Transcription; Genomic approach; Genomics; Glioma; Histone H3; Location; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic; Missense Mutation; Modeling; Molecular; Mutation; Names; Nucleosomes; Patients; Prognosis; Property; Proteins; Proteomics; Recurrence; Regulation; Reporting; Resolution; Role; Running; Signal Transduction; Structure; Telomere Maintenance; Telomere Pathway; Time; cancer cell; chromatin remodeling; cytotoxicity; epigenome; epithelial to mesenchymal transition; gain of function; genome integrity; histone modification; improved; innovation; loss of function mutation; prevent; promoter; public health relevance; reconstitution; recruit; repaired; replication stress; response; targeted cancer therapy; telomere; therapeutic target; trait; tumor

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.

摘要 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是一种专门的 同源性定向修复（HDR）机制致力于修复和延长端粒，从而确保端粒的完整性。 这些癌细胞的增殖永生。基因编码的反复失活错义突变 ATRX-DAXX染色质重塑/组蛋白H3.3沉积复合物与 其中ALT被激活的肿瘤，两者都在转移性疾病晚期出现。这些丧失功能的突变 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被认为刺激ALT相关的HDR。而人类发展报告机制 已经对ALT的基础进行了广泛的研究，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也获得转移性特征仍然不明确。这项建议 基于我们最近的报告，在ATRX-DAXX（一种已知的相关染色质组装因子）失活后， 由于HIRA对于ALT癌症中的从头组蛋白H3.3沉积和端粒延伸变得不可或缺， 细胞此外，我们发现HIRA的耗竭引起ATRX-DAXX的急性全身性死亡， 缺陷细胞引人注目的是，这种细胞毒性通过用野生型ATRX重建ALT细胞而逆转 蛋白这些数据为HIRA采用的补偿功能提供了令人信服的证据， ATRX-DAXX缺陷可以用来消除ALT癌细胞。