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POT1失活诱导的端粒复制应激加速肿瘤发生。

Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis.

作者信息

Pinzaru Alexandra M, Hom Robert A, Beal Angela, Phillips Aaron F, Ni Eric, Cardozo Timothy, Nair Nidhi, Choi Jaehyuk, Wuttke Deborah S, Sfeir Agnel, Denchi Eros Lazzerini

机构信息

Department of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY 10016, USA.

Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.

出版信息

Cell Rep. 2016 Jun 7;15(10):2170-2184. doi: 10.1016/j.celrep.2016.05.008. Epub 2016 May 26.

DOI:10.1016/j.celrep.2016.05.008
PMID:27239034
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6145145/
Abstract

Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.

摘要

基因组测序研究已经揭示了端粒结合因子POT1中一些与癌症相关的突变。在此，我们表明，当与p53缺陷相结合时，在普通淋巴祖细胞中缺失小鼠POT1a会促进基因不稳定，加速T细胞淋巴瘤的发病，并增加其严重程度。同时，我们研究了携带在皮肤T细胞淋巴瘤（CTCL）患者中发现的POT1突变的人类和小鼠细胞。抑制POT1会激活ATR依赖性DNA损伤信号传导，并诱导端粒脆性、复制叉停滞和端粒延长。我们的数据表明，这些表型与端粒处受损的CST（CTC1-STN1-TEN1）功能有关。最后，我们表明，缺乏POT1的癌细胞的增殖是由ATR激酶途径的减弱所促成的。这些结果揭示了肿瘤发生过程中端粒复制缺陷的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/a79d2cca37c9/nihms-987148-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/05817ebd4b82/nihms-987148-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/03f05fe45566/nihms-987148-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/598d22ed9318/nihms-987148-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/eea590258fdf/nihms-987148-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/45caaee11e7e/nihms-987148-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/433c6243227a/nihms-987148-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/a79d2cca37c9/nihms-987148-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/05817ebd4b82/nihms-987148-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/03f05fe45566/nihms-987148-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/598d22ed9318/nihms-987148-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/eea590258fdf/nihms-987148-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/45caaee11e7e/nihms-987148-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/433c6243227a/nihms-987148-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/506a/6145145/a79d2cca37c9/nihms-987148-f0007.jpg

相似文献

[1]
Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis.

Cell Rep. 2016-6-7

[2]
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[3]
Protection of telomeres 1 proteins POT1a and POT1b can repress ATR signaling by RPA exclusion, but binding to CST limits ATR repression by POT1b.

J Biol Chem. 2018-8-6

[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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Exp Hematol Oncol. 2025-1-27

[2]
Germline predisposition in multiple myeloma.

iScience. 2024-12-17

[3]
Telomere function and regulation from mouse models to human ageing and disease.

Nat Rev Mol Cell Biol. 2025-4

[4]
Telomere maintenance and the DNA damage response: a paradoxical alliance.

Front Cell Dev Biol. 2024-10-17

[5]
The Tumor Microenvironment as a Therapeutic Target in Cutaneous T Cell Lymphoma.

Cancers (Basel). 2024-10-1

[6]
Telomeres and telomerase in Sarcoma disease and therapy.

Int J Med Sci. 2024

[7]
Single nucleotide polymorphism profiles of canine T-cell and null-cell lymphomas.

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[8]
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Nucleic Acids Res. 2024-9-9

[9]
Telomere dynamics and oxidative stress in Arabidopsis grown in lunar regolith simulant.

Front Plant Sci. 2024-2-16

[10]
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本文引用的文献

[1]
Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.

Oncotarget. 2015-12-15

[2]
ATM and ATR Signaling Regulate the Recruitment of Human Telomerase to Telomeres.

Cell Rep. 2015-11-24

[3]
A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families.

Nat Commun. 2015-9-25

[4]
Genomic landscape of cutaneous T cell lymphoma.

Nat Genet. 2015-9

[5]
Gene dosage reductions of Trf1 and/or Tin2 induce telomere DNA damage and lymphoma formation in aging mice.

Leukemia. 2016-3

[6]
Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients.

Mol Oncol. 2015-6

[7]
Germline mutations in shelterin complex genes are associated with familial glioma.

J Natl Cancer Inst. 2014-12-7

[8]
TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling.

Genes Dev. 2014-11-15

[9]
POT1a and components of CST engage telomerase and regulate its activity in Arabidopsis.

PLoS Genet. 2014-10-16

[10]
Replication stress and cancer: it takes two to tango.

Exp Cell Res. 2014-11-15

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