CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion

被引：138

作者：

Gu, Peili ^{[1
]}

Min, Jin-Na ^{[1
]}

Wang, Yang ^{[1
]}

Huang, Chenhui ^{[2
]}

Peng, Tao ^{[3
]}

Chai, Weihang ^{[2
]}

Chang, Sandy ^{[1
]}

机构：

[1] Yale Univ, Dept Lab Med & Pathol, Sch Med, New Haven, CT 06520 USA

[2] Washington State Univ, Sch Mol Biosci, Spokane, WA USA

[3] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Cardiol, Houston, TX USA

来源：

EMBO JOURNAL | 2012年 / 31卷 / 10期

关键词：

DNA damage; DNA replication; mouse model; stem cell; telomere; DNA-POLYMERASE-ALPHA; SINGLE-STRANDED-DNA; HOMOLOGOUS RECOMBINATION; CATALYTIC SUBUNIT; FAMILIAL SYNDROME; BINDING PROTEIN; DAMAGE RESPONSE; COMPONENT; CDC13; COMPLEX;

D O I：

10.1038/emboj.2012.96

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The proper maintenance of telomeres is essential for genome stability. Mammalian telomere maintenance is governed by a number of telomere binding proteins, including the newly identified CTC1-STN1-TEN1 (CST) complex. However, the in vivo functions of mammalian CST remain unclear. To address this question, we conditionally deleted CTC1 from mice. We report here that CTC1 null mice experience rapid onset of global cellular proliferative defects and die prematurely from complete bone marrow failure due to the activation of an ATR-dependent G2/M checkpoint. Acute deletion of CTC1 does not result in telomere deprotection, suggesting that mammalian CST is not involved in capping telomeres. Rather, CTC1 facilitates telomere replication by promoting efficient restart of stalled replication forks. CTC1 deletion results in increased loss of leading C-strand telomeres, catastrophic telomere loss and accumulation of excessive ss telomere DNA. Our data demonstrate an essential role for CTC1 in promoting efficient replication and length maintenance of telomeres. The EMBO Journal (2012) 31, 2309-2321. doi: 10.1038/emboj.2012.96; Published online 24 April 2012

引用

页码：2309 / 2321

页数：13

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