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TRF2 促进结合端粒突出部的 POT1 动态和逐步环化。

TRF2 promotes dynamic and stepwise looping of POT1 bound telomeric overhang.

机构信息

Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA.

Department of Environmental and Occupational Health, University of Pittsburgh, Hillman Cancer Center, 5117 Centre Avenue, Suite 2.6a, Pittsburgh, PA 15213, USA.

出版信息

Nucleic Acids Res. 2021 Dec 2;49(21):12377-12393. doi: 10.1093/nar/gkab1123.

DOI:10.1093/nar/gkab1123
PMID:34850123
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8643667/
Abstract

Human telomeres are protected by shelterin proteins, but how telomeres maintain a dynamic structure remains elusive. Here, we report an unexpected activity of POT1 in imparting conformational dynamics of the telomere overhang, even at a monomer level. Strikingly, such POT1-induced overhang dynamics is greatly enhanced when TRF2 engages with the telomere duplex. Interestingly, TRF2, but not TRF2ΔB, recruits POT1-bound overhangs to the telomere ds/ss junction and induces a discrete stepwise movement up and down the axis of telomere duplex. The same steps are observed regardless of the length of the POT1-bound overhang, suggesting a tightly regulated conformational dynamic coordinated by TRF2 and POT1. TPP1 and TIN2 which physically connect POT1 and TRF2 act to generate a smooth movement along the axis of the telomere duplex. Our results suggest a plausible mechanism wherein telomeres maintain a dynamic structure orchestrated by shelterin.

摘要

人类端粒受端粒保护蛋白（shelterin proteins）的保护，但端粒如何维持动态结构仍难以捉摸。在这里，我们报告了 POT1 赋予端粒突出端构象动力学的意外活性，即使在单体水平也是如此。引人注目的是，当 TRF2 与端粒双链结合时，这种 POT1 诱导的突出端动力学大大增强。有趣的是，TRF2（而不是 TRF2ΔB）将 POT1 结合的突出端募集到端粒 ds/ss 连接点，并诱导沿着端粒双链轴的离散逐步上下移动。无论 POT1 结合的突出端的长度如何，都观察到相同的步骤，表明 TRF2 和 POT1 协调的严格调节构象动态。物理上连接 POT1 和 TRF2 的 TPP1 和 TIN2 可沿端粒双链轴产生平滑运动。我们的结果表明了一种合理的机制，即端粒通过庇护所维持动态结构。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/a2c604a7bc9a/gkab1123fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/d55a70293447/gkab1123fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/e8c1fb47da88/gkab1123fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/d5c788a58be4/gkab1123fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/4f816152ac6c/gkab1123fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/9505d3ada514/gkab1123fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/daab6aec84fe/gkab1123fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/d32f1ff610aa/gkab1123fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/a2c604a7bc9a/gkab1123fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/d55a70293447/gkab1123fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/e8c1fb47da88/gkab1123fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/d5c788a58be4/gkab1123fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/4f816152ac6c/gkab1123fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/9505d3ada514/gkab1123fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/daab6aec84fe/gkab1123fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/d32f1ff610aa/gkab1123fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c444/8643667/a2c604a7bc9a/gkab1123fig8.jpg

相似文献

[1]
TRF2 promotes dynamic and stepwise looping of POT1 bound telomeric overhang.

Nucleic Acids Res. 2021-12-2

[2]
TRF2-tethered TIN2 can mediate telomere protection by TPP1/POT1.

Mol Cell Biol. 2014-1-27

[3]
TIN2 is an architectural protein that facilitates TRF2-mediated trans- and cis-interactions on telomeric DNA.

Nucleic Acids Res. 2021-12-16

[4]
In vivo stoichiometry of shelterin components.

J Biol Chem. 2009-10-28

[5]
Human Telomere Repeat Binding Factor TRF1 Replaces TRF2 Bound to Shelterin Core Hub TIN2 when TPP1 Is Absent.

J Mol Biol. 2019-5-31

[6]
Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex.

Cell Res. 2017-11-21

[7]
Shelterin proteins and cancer.

Asian Pac J Cancer Prev. 2015

[8]
POT1 association with TRF2 regulates telomere length.

Mol Cell Biol. 2009-10

[9]
The evolution of metazoan shelterin.

Genes Dev. 2021-12-1

[10]
Structure, dynamics, and regulation of TRF1-TIN2-mediated trans- and cis-interactions on telomeric DNA.

J Biol Chem. 2021-9

引用本文的文献

[1]
Mechanistic insights into direct DNA and RNA strand transfer and dynamic protein exchange of SSB and RPA.

Nucleic Acids Res. 2025-6-20

[2]
Simultaneous probing of transcription, G-quadruplex, and R-loop.

Methods Enzymol. 2024

[3]
The molecular mechanism for TERRA recruitment and annealing to telomeres.

Nucleic Acids Res. 2024-9-23

[4]
BG4 antibody can recognize telomeric G-quadruplexes harboring destabilizing base modifications and lesions.

Nucleic Acids Res. 2024-2-28

[5]
Human POT1 protects the telomeric ds-ss DNA junction by capping the 5' end of the chromosome.

Science. 2023-8-18

[6]
Emerging accessibility patterns in long telomeric overhangs.

Proc Natl Acad Sci U S A. 2022-7-26

[7]
Structural biology of CRISPR-Cas immunity and genome editing enzymes.

Nat Rev Microbiol. 2022-11

[8]
Protocol for generation and regeneration of PEG-passivated slides for single-molecule measurements.

STAR Protoc. 2022-3-18

本文引用的文献

[1]
A Helicase Unwinds Hexanucleotide Repeat RNA G-Quadruplexes and Facilitates Repeat-Associated Non-AUG Translation.

J Am Chem Soc. 2021-5-19

[2]
Regeneration of PEG slide for multiple rounds of single-molecule measurements.

Biophys J. 2021-5-4

[3]
Position-Dependent Effect of Guanine Base Damage and Mutations on Telomeric G-Quadruplex and Telomerase Extension.

Biochemistry. 2020-7-21

[4]
Characterization of t-loop formation by TRF2.

Nucleus. 2020-12

[5]
Single-Molecule Imaging of Telomerase RNA Reveals a Recruitment-Retention Model for Telomere Elongation.

Mol Cell. 2020-6-3

[6]
E. coli Rep helicase and RecA recombinase unwind G4 DNA and are important for resistance to G4-stabilizing ligands.

Nucleic Acids Res. 2020-7-9

[7]
RNA G-quadruplex is resolved by repetitive and ATP-dependent mechanism of DHX36.

Nat Commun. 2019-4-23

[8]
Shelterin-Mediated Telomere Protection.

Annu Rev Genet. 2018-9-12

[9]
Telomere Loop Dynamics in Chromosome End Protection.

Mol Cell. 2018-7-19

[10]
Direct observation of the external force mediated conformational dynamics of an IHF bound Holliday junction.

Faraday Discuss. 2018-4-17

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