Elucidation of the consequence of telomere single-stand overhang, G-tail, in biology, and application to age-related disease

阐明端粒单链突出（G 尾）在生物学中的影响及其在年龄相关疾病中的应用

• 批准号: 18390027
• 负责人: TAHARA Hidetoshi
• 金额: $ 10.66万
• 依托单位: Hiroshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390027/
• 关键词: telomere; G-tail; telomere binding protein; telomerase; anticancer drug; 老化; 抗癌剤耐性

(1) Conditiona deletion of mouse Potla induces a DNA damage response at telomeres, resulting in p53-dependent replicative senescence. Potla-deficient cells exhibit overall telomere length and 3' overhang elongation as well as aberrant homologous recombination (HR) at telomeres, manifested as increased telomere sister chromatid exchanges and formation of telomere circles.(2) We found that G-tail length were reduce in fibroblats, hetatocytes and HUVEC cells with cellular senescence. When forced expression of hTERT gene into these human normal cells, both telomere G-tail and total telomere length were elongated.(3) The wild-type FN-tankyrase 1 increased the G-tail size to 134% of the mock cell line. FN-tank-ARC IVmut-ΔARC V also elongated the G-tail to 123% of the mock line. Collectively, reduced POT1 binding and increased G-tail length would reflect higher accessibility of telomerase to telomeres.Further study of telomere associated proteins including shelterin complex (TRF1, TRF2, TIN2, PTOP, POT1, RAP1, Apollo) is important for the elucidation of genomic instability as well as genomic integrity in human disease such as cancer and aging.

(1)小鼠Potla的条件a缺失诱导端粒DNA损伤反应，导致p53依赖性复制衰老。Potla缺陷细胞表现出总体端粒长度和3'突出端延长以及端粒处的异常同源重组（HR），表现为增加的端粒姐妹染色单体交换和端粒环的形成。(2)我们发现，随着细胞衰老，成纤维细胞、肝细胞和HUVEC细胞的G-尾长度减少。当hTERT基因强制表达到这些人类正常细胞中时，端粒G-尾和端粒总长度都延长。(3)野生型FN端锚聚合酶1将G-尾大小增加至模拟细胞系的134%。FN-tank-ARC IVmut-ΔARC V也将G尾延长至模拟线的123%。进一步研究端粒相关蛋白包括shelterin complex（TRF 1，TRF 2，TIN 2，PTOP，POT 1，RAP 1，Apollo）对阐明人类疾病如癌症和衰老中基因组的不稳定性以及基因组的完整性具有重要意义。

项目成果

Telomerase activation induces elongation of the telomeric single-stranded overhang, but does not prevent chromosome aberratio in human vascular endothelial cells.

端粒酶激活可诱导端粒单链突出端的延长，但不能防止人血管内皮细胞中的染色体畸变。

• 发表时间: 2007
• 期刊: Biochemical and Biophysical Research Communications 353
• 作者: Anno;K.
• 通讯作者: K.

Application of telomere G-tail assay for analysis of clinical patient samples

端粒 G 尾测定在临床患者样本分析中的应用

• 发表时间: 2008
• 作者: Aoki;E
• 通讯作者: E

臨床検体を用いたG-tail assay法の開発

使用临床样本开发 G 尾检测方法

• 发表时间: 2008
• 作者: Kondo T;Hori Y;Yatsuya H;Tamakoshi K;Toyoshima H;Nishino Y;Seki N;ItoY;Suzuki K;OzasaK;Watanabe Y;Ando M;Wakai K;Tamakoshi A;for the JACC Study Group;青木 絵里子
• 通讯作者: 青木 絵里子

HTERT INDUCES TELOMERE G-TAIL ELONGATION AND MAINTAINS NORMAL CELLULAR CHARACTERISTICS IN HUVECS

HTERT 诱导端粒 G 尾伸长并维持 HUVECS 的正常细胞特征

• 发表时间: 2007
• 作者: Anno;K
• 通讯作者: K

POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination

• DOI: 10.1038/sj.emboj.7601294
• 发表时间: 2006-11-01
• 期刊: EMBO JOURNAL
• 影响因子: 11.4
• 作者: He, Hua;Multani, Asha S.;Chang, Sandy
• 通讯作者: Chang, Sandy