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人类 CST 复合物是端粒酶活性的终结者。

The human CST complex is a terminator of telomerase activity.

机构信息

Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne, Station 19, 1015 Lausanne, Switzerland.

出版信息

Nature. 2012 Aug 23;488(7412):540-4. doi: 10.1038/nature11269.


DOI:10.1038/nature11269
PMID:22763445
Abstract

The lengths of human telomeres, which protect chromosome ends from degradation and end fusions, are crucial determinants of cell lifespan. During embryogenesis and in cancer, the telomerase enzyme counteracts telomeric DNA shortening. As shown in cancer cells, human telomerase binds the shelterin component TPP1 at telomeres during the S phase of the cell cycle, and adds ~60 nucleotides in a single round of extension, after which telomerase is turned off by unknown mechanisms. Here we show that the human CST (CTC1, STN1 and TEN1) complex, previously implicated in telomere protection and DNA metabolism, inhibits telomerase activity through primer sequestration and physical interaction with the protection of telomeres 1 (POT1)–TPP1 telomerase processivity factor. CST competes with POT1–TPP1 for telomeric DNA, and CST–telomeric-DNA binding increases during late S/G2 phase only on telomerase action, coinciding with telomerase shut-off. Depletion of CST allows excessive telomerase activity, promoting telomere elongation. We propose that through binding of the telomerase-extended telomere, CST limits telomerase action at individual telomeres to approximately one binding and extension event per cell cycle. Our findings define the sequence of events that occur to first enable and then terminate telomerase-mediated telomere elongation.

摘要

人类端粒的长度决定了细胞寿命,端粒是保护染色体末端免受降解和融合的关键因素。在胚胎发生和癌症中,端粒酶可抵抗端粒 DNA 的缩短。如在癌细胞中所显示的,人端粒酶在细胞周期的 S 期与端粒结合 shelterin 成分 TPP1,并在单个延伸轮中添加约 60 个核苷酸,之后端粒酶通过未知机制关闭。在这里,我们表明,先前涉及端粒保护和 DNA 代谢的人类 CST(CTC1、STN1 和 TEN1)复合物通过引物隔离和与端粒保护蛋白 1(POT1)-TPP1 端粒酶延伸因子的物理相互作用来抑制端粒酶活性。CST 与 POT1-TPP1 竞争端粒 DNA,并且仅在端粒酶作用下,CST 与端粒-DNA 的结合在 S/G2 晚期增加,这与端粒酶失活同时发生。CST 的耗竭允许过度的端粒酶活性,从而促进端粒的延长。我们提出,通过结合端粒酶延伸的端粒,CST 将端粒酶在单个端粒上的作用限制为每个细胞周期约一次结合和延伸事件。我们的发现定义了首先使端粒酶介导的端粒延伸能够发生,然后终止端粒酶介导的端粒延伸的一系列事件。

相似文献

[1]
The human CST complex is a terminator of telomerase activity.

Nature. 2012-8-23

[2]
The POT1-TPP1 telomere complex is a telomerase processivity factor.

Nature. 2007-2-1

[3]
TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase.

Nature. 2007-2-1

[4]
POT1 recruits and regulates CST-Polα/primase at human telomeres.

Cell. 2024-7-11

[5]
The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity.

Nature. 2012-10-24

[6]
In vivo stoichiometry of shelterin components.

J Biol Chem. 2009-10-28

[7]
CTC1 OB-B interaction with TPP1 terminates telomerase and prevents telomere overextension.

Nucleic Acids Res. 2023-6-9

[8]
SUMOylation regulates telomere length by targeting the shelterin subunit Tpz1(Tpp1) to modulate shelterin-Stn1 interaction in fission yeast.

Proc Natl Acad Sci U S A. 2014-4-7

[9]
The fission yeast Stn1-Ten1 complex limits telomerase activity via its SUMO-interacting motif and promotes telomeres replication.

Sci Adv. 2018-5-16

[10]
Structural biology of telomeres and telomerase.

Cell Mol Life Sci. 2019-11-14

引用本文的文献

[1]
The - Mutant Provides New Insight into the Impacts of Telomeric Cdc13-Stn1-Ten1 Dysfunction on Cell Cycle Progression.

Cells. 2025-5-26

[2]
Gene Expression Analysis of (Paired) Primary and Relapsed Wilms Tumor Samples to Unravel the Underlying Factors Driving Tumor Recurrence.

Cancer Med. 2025-6

[3]
The yeast CST and Polα/primase complexes act in concert to ensure proper telomere maintenance and protection.

Nucleic Acids Res. 2025-4-10

[4]
Loss of Ten1 in mice induces telomere shortening and models human dyskeratosis congenita.

Sci Adv. 2025-4-11

[5]
Association of metallic elements with telomere length in children with autism spectrum disorder.

PeerJ. 2025-4-1

[6]
Rapid dynamics allow the low-abundance RTEL1 helicase to promote telomere replication.

Nucleic Acids Res. 2025-2-27

[7]
Canonical and non-canonical functions of the non-coding RNA component (TERC) of telomerase complex.

Cell Biosci. 2025-3-1

[8]
Telomere function and regulation from mouse models to human ageing and disease.

Nat Rev Mol Cell Biol. 2025-4

[9]
Telomeres: an organized string linking plants and mammals.

Biol Direct. 2024-11-20

[10]
Telomere maintenance and the DNA damage response: a paradoxical alliance.

Front Cell Dev Biol. 2024-10-17

本文引用的文献

[1]
CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion.

EMBO J. 2012-4-24

[2]
Xenopus laevis Ctc1-Stn1-Ten1 (xCST) protein complex is involved in priming DNA synthesis on single-stranded DNA template in Xenopus egg extract.

J Biol Chem. 2011-11-14

[3]
Processive and distributive extension of human telomeres by telomerase under homeostatic and nonequilibrium conditions.

Mol Cell. 2011-5-6

[4]
Telomeric strategies: means to an end.

Annu Rev Genet. 2010

[5]
TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo.

Mol Cell Biol. 2010-4-19

[6]
POT1-TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation.

EMBO J. 2010-1-21

[7]
How telomeres solve the end-protection problem.

Science. 2009-11-13

[8]
Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes.

Mol Cell. 2009-10-23

[9]
RPA-like mammalian Ctc1-Stn1-Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway.

Mol Cell. 2009-10-23

[10]
Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells.

Cell. 2009-8-7

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