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53BP1 缺失与端粒功能障碍激活 ATR 依赖性 DNA 损伤反应。

53BP1 deficiency combined with telomere dysfunction activates ATR-dependent DNA damage response.

机构信息

Telomeres and Telomerase Group, Molecular Oncology Programme, Spanish National Cancer Research Centre, E-28029 Madrid, Spain.

出版信息

J Cell Biol. 2012 Apr 16;197(2):283-300. doi: 10.1083/jcb.201110124.

DOI:10.1083/jcb.201110124
PMID:22508511
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3328378/
Abstract

TRF1 protects mammalian telomeres from fusion and fragility. Depletion of TRF1 leads to telomere fusions as well as accumulation of γ-H2AX foci and activation of both the ataxia telangiectasia mutated (ATM)- and the ataxia telangiectasia and Rad3 related (ATR)-mediated deoxyribonucleic acid (DNA) damage response (DDR) pathways. 53BP1, which is also present at dysfunctional telomeres, is a target of ATM that accumulates at DNA double-strand breaks and favors nonhomologous end-joining (NHEJ) repair over ATM-dependent resection and homology-directed repair (homologous recombination [HR]). To address the role of 53BP1 at dysfunctional telomeres, we generated mice lacking TRF1 and 53BP1. 53BP1 deficiency significantly rescued telomere fusions in mouse embryonic fibroblasts (MEFs) lacking TRF1, but they showed evidence of a switch from the NHEJ- to HR-mediated repair of uncapped telomeres. Concomitantly, double-mutant MEFs showed evidence of hyperactivation of the ATR-dependent DDR. In intact mice, combined 53BP1/TRF1 deficiency in stratified epithelia resulted in earlier onset of DNA damage and increased CHK1 phosphorylation during embryonic development, leading to aggravation of skin phenotypes.

摘要

TRF1 保护哺乳动物端粒免受融合和脆弱性的影响。TRF1 的耗竭会导致端粒融合，以及 γ-H2AX 焦点的积累，以及共济失调毛细血管扩张突变（ATM）和共济失调毛细血管扩张和 Rad3 相关（ATR）介导的脱氧核糖核酸（DNA）损伤反应（DDR）途径的激活。53BP1 也存在于功能失调的端粒上，是 ATM 的靶标，在 DNA 双链断裂处积累，并有利于非同源末端连接（NHEJ）修复，而不是 ATM 依赖性切除和同源定向修复（同源重组[HR]）。为了研究 53BP1 在功能失调的端粒上的作用，我们生成了缺乏 TRF1 和 53BP1 的小鼠。53BP1 缺陷显著挽救了缺乏 TRF1 的小鼠胚胎成纤维细胞（MEF）中的端粒融合，但它们显示出从无帽端粒的 NHEJ 介导修复向 HR 介导修复转变的证据。同时，双突变 MEF 显示出 ATR 依赖性 DDR 的过度激活的证据。在完整的小鼠中，在分层上皮细胞中同时缺乏 53BP1/TRF1 会导致胚胎发育过程中更早出现 DNA 损伤和 CHK1 磷酸化增加，从而加重皮肤表型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/f93dc85395e2/JCB_201110124_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/3c082a162e57/JCB_201110124_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/2122c42ff6a9/JCB_201110124_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/e255b4c073a3/JCB_201110124_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/d4d9311cb135/JCB_201110124_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/3f2e41810a7b/JCB_201110124_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/cc82539f57cb/JCB_201110124_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/f8f730b975b9/JCB_201110124_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/16e5a52cbb6e/JCB_201110124_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/92ca7473e93a/JCB_201110124_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/f93dc85395e2/JCB_201110124_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/3c082a162e57/JCB_201110124_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/2122c42ff6a9/JCB_201110124_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/e255b4c073a3/JCB_201110124_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/d4d9311cb135/JCB_201110124_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/3f2e41810a7b/JCB_201110124_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/cc82539f57cb/JCB_201110124_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/f8f730b975b9/JCB_201110124_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/16e5a52cbb6e/JCB_201110124_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/92ca7473e93a/JCB_201110124_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/41c0/3328378/f93dc85395e2/JCB_201110124_Fig10.jpg

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本文引用的文献

[1]
Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins.

Nat Rev Cancer. 2011-3

[2]
The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres.

EMBO J. 2010-6-29

[3]
Role of shelterin in cancer and aging.

Aging Cell. 2010-7-22

[4]
TPP1 is required for TERT recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice.

Dev Cell. 2010-5-18

[5]
53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers.

Nat Struct Mol Biol. 2010-5-9

[6]
53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks.

Cell. 2010-4-1

[7]
Loss of Rap1 induces telomere recombination in the absence of NHEJ or a DNA damage signal.

Science. 2010-3-26

[8]
p53 prevents entry into mitosis with uncapped telomeres.

Curr Biol. 2010-3-11

[9]
Telomere protection by TPP1 is mediated by POT1a and POT1b.

Mol Cell Biol. 2009-12-7

[10]
How telomeres solve the end-protection problem.

Science. 2009-11-13

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