Telomere attrition in premature aging syndromes

早衰综合征中的端粒磨损

• 批准号: 7964040
• 负责人: Yie Liu
• 金额: $ 25.34万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964040
• 关键词: Affinity Chromatography; Cell Death; Cells; DNA Damage; DNA Repair; Data; Defect; Disease; Fanconi anemia protein; Fanconi' s Anemia; Genes; Helicase Gene; Hematologic Neoplasms; Hematopoietic; Human; Mutate; Mutation; Pancytopenia; Patients; Premature aging syndrome; Process; RECQL4 gene; Reporting; Research; Role; Screening procedure; Telomere Length Maintenance; Telomere Shortening; age related; base; early onset; helicase; human SKIV2L protein; human disease; in vivo; novel; tandem mass spectrometry; telomere

The project includes two parts: 1) Mutations in RecQ-helicase genes, BLM, WRN, and RECQ4 associate with autosomal recessive premature aging disorders. RecQ helicase deficient human cells have an increased level of DNA damage and/or telomere attrition. We are in the process to examine the role of RecQ helicases in telomere DNA damage repair and telomere length maintenance in human cells. In addition, we are screening for helicase-like proteins that associate with telomeres by dual-tag based affinity purification in combination with tandem mass spectrometry approach. 2) Fanconi anemia (FA) is an autosomal recessive disorder. FANCC is one of commonly mutated FA genes in FA patients and the FANCC subtype tends to associate with early onset of bone-marrow failure and hematologic malignancies. Prior reports showed telomere shortening in patients with Fanconi anemia. We have initiated the studies on the role of FANCC in telomere length maintenance in vivo. Our preliminary data suggest that FANCC may suppress telomere attrition, thus limiting hematopoietic cell death or immortalization. These studies will unveil potential novel mechanism(s) of how helicase and FA proteins may impact telomere integrity and thus age-related disease.

该项目包括两个部分： 1）RECQ-螺旋酶基因，BLM，WRN和RECQ4的突变与常染色体隐性过早衰老疾病有关。 RECQ解旋酶缺乏的人类细胞具有DNA损伤和/或端粒损耗的水平增加。我们正在研究RECQ解旋酶在人类细胞中端粒DNA损伤修复和端粒长度维持中的作用。此外，我们还筛选了类似于端粒的蛋白质与端粒相关的蛋白质，并结合串联质谱法结合使用。 2）Fanconi贫血（FA）是常染色体隐性疾病。 FANCC是FA患者常见突变的FA基因之一，FANCC亚型倾向于与骨髓衰竭和血液学恶性肿瘤的早期发作相关。先前的报告显示，范科尼贫血患者的端粒缩短。我们已经启动了FANCC在体内长度维持中的作用的研究。我们的初步数据表明，FANCC可能会抑制端粒损耗，从而限制造血细胞死亡或永生化。 这些研究将公布潜在的新型机制，即解旋酶和FA蛋白如何影响端粒完整性，从而影响与年龄相关的疾病。