期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 45, 页码 17747-17752出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0706485104
关键词
apoptosis; cell cycle; DNA damage; stem cells; telomerase
资金
- NCI NIH HHS [R01 CA111691] Funding Source: Medline
- NIDDK NIH HHS [P30 DK56339, P30 DK056339] Funding Source: Medline
Telomeres protect chromosome ends and serve as a substrate for telomerase, a reverse transcriptase that adds DNA repeats to the telomere terminus. In the absence of telomerase, telomeres progressively shorten, ultimately leading to telomere uncapping, a structural change at the telomere that activates DNA damage responses and leads to ligation of chromosome ends. Telomere uncapping has been implicated in aging and cancer, yet the precise mechanism of uncapping and its relationship to cell cycle remain to be defined. Here, we show that telomeres uncap in an S-phase-d e pendent manner in gastrointestinal progenitors of TERT-/- mice. We develop an in vivo assay that allows a quantitative kinetic assessment of telomere dysfunction-induced apoptosis and its relationship to cell cycle. By exploiting the mathematical relationship between rates of generation and clearance of apoptotic cells, we show that 86.2 +/- 8.8% of apoptotic gastrointestinal cells undergo programmed cell death either late in S-phase or in G(2). Apoptosis is primarily triggered via a signaling cascade from newly uncapped telomeres to the tumor suppressor p53, rather than by chromosome fusion-bridge breakage, because mitotic blockade did not alter the rate of newly generated apoptotic bodies. These data support a model in which rapidly dividing progenitor cells within a tissue with short telomeres are vulnerable to telomere uncapping during or shortly after telomere replication.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据