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端粒处 HP1alpha 的局部富集改变了端粒的结构和对端粒保护的调控。

Local enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection.

机构信息

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94143, USA.

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94143, USA.

出版信息

Nat Commun. 2018 Sep 4;9(1):3583. doi: 10.1038/s41467-018-05840-y.


DOI:10.1038/s41467-018-05840-y
PMID:30181605
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6123478/
Abstract

Enhanced telomere maintenance is evident in malignant cancers. While telomeres are thought to be inherently heterochromatic, detailed mechanisms of how epigenetic modifications impact telomere protection and structures are largely unknown in human cancers. Here we develop a molecular tethering approach to experimentally enrich heterochromatin protein HP1α specifically at telomeres. This results in increased deposition of H3K9me3 at cancer cell telomeres. Telomere extension by telomerase is attenuated, and damage-induced foci at telomeres are reduced, indicating augmentation of telomere stability. Super-resolution STORM imaging shows an unexpected increase in irregularity of telomeric structure. Telomere-tethered chromo shadow domain (CSD) mutant I165A of HP1α abrogates both the inhibition of telomere extension and the irregularity of telomeric structure, suggesting the involvement of at least one HP1α-ligand in mediating these effects. This work presents an approach to specifically manipulate the epigenetic status locally at telomeres to uncover insights into molecular mechanisms underlying telomere structural dynamics.

摘要

端粒维持增强在恶性癌症中显而易见。虽然端粒被认为是固有异染色质,但在人类癌症中,表观遗传修饰如何影响端粒保护和结构的详细机制在很大程度上尚不清楚。在这里,我们开发了一种分子系绳方法,可特异性地在端粒上实验性富集异染色质蛋白 HP1α。这导致 H3K9me3 在癌细胞端粒上的沉积增加。端粒酶介导的端粒延伸受到抑制,并且端粒处的损伤诱导焦点减少,表明端粒稳定性增强。超分辨率 STORM 成像显示端粒结构的不规则性出人意料地增加。HP1α 的端粒结合染色质阴影域(CSD)突变 I165A 既消除了端粒延伸的抑制作用,也消除了端粒结构的不规则性,表明至少有一个 HP1α 配体参与介导这些效应。这项工作提出了一种专门在端粒处局部操纵表观遗传状态的方法,以揭示端粒结构动力学的分子机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/06ec3d755e05/41467_2018_5840_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/67057cbcdfe3/41467_2018_5840_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/4705be0694f7/41467_2018_5840_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/1feac3a9b6af/41467_2018_5840_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/21bd4a4c761c/41467_2018_5840_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/45ae7c78fb85/41467_2018_5840_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/c36200a5762d/41467_2018_5840_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/06ec3d755e05/41467_2018_5840_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/67057cbcdfe3/41467_2018_5840_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/4705be0694f7/41467_2018_5840_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/1feac3a9b6af/41467_2018_5840_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/21bd4a4c761c/41467_2018_5840_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/45ae7c78fb85/41467_2018_5840_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/c36200a5762d/41467_2018_5840_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff3e/6123478/06ec3d755e05/41467_2018_5840_Fig7_HTML.jpg

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引用本文的文献

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[2]
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[3]
Non-random spatial organization of telomeres varies during the cell cycle and requires LAP2 and BAF.

iScience. 2024-2-28

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Telomerase in Cancer: Function, Regulation, and Clinical Translation.

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[5]
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[6]
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[7]
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[8]
Unravelling HP1 functions: post-transcriptional regulation of stem cell fate.

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[9]
Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interaction.

Cell Rep. 2021-5-18

[10]
In Situ Detection of Complex DNA Damage Using Microscopy: A Rough Road Ahead.

Cancers (Basel). 2020-11-6

本文引用的文献

[1]
Epigenetic features of human telomeres.

Nucleic Acids Res. 2018-3-16

[2]
Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome.

Nat Cell Biol. 2017-10

[3]
Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin.

Nature. 2017-7-13

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Genes Dev. 2017-3-15

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Genes Dev. 2017-3-15

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Cell. 2016-8-25

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Nucleic Acids Res. 2015-12-2

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Nat Commun. 2015-7-24

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