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DNA 微环阐明了 DNA 结构在逆转录病毒整合中的特定作用。

DNA minicircles clarify the specific role of DNA structure on retroviral integration.

作者信息

Pasi Marco, Mornico Damien, Volant Stevenn, Juchet Anna, Batisse Julien, Bouchier Christiane, Parissi Vincent, Ruff Marc, Lavery Richard, Lavigne Marc

机构信息

MMSB UMR5086 University of Lyon I/CNRS, Institut de Biologie et Chimie des Protéines, 7 passage du Vercors, Lyon 69367, France.

Institut Pasteur-Bioinformatics and Biostatistics Hub-C3BI, USR 3756 IP-CNRS, Paris 75015, France.

出版信息

Nucleic Acids Res. 2016 Sep 19;44(16):7830-47. doi: 10.1093/nar/gkw651. Epub 2016 Jul 20.

DOI:10.1093/nar/gkw651
PMID:27439712
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5027509/
Abstract

Chromatin regulates the selectivity of retroviral integration into the genome of infected cells. At the nucleosome level, both histones and DNA structure are involved in this regulation. We propose a strategy that allows to specifically study a single factor: the DNA distortion induced by the nucleosome. This strategy relies on mimicking this distortion using DNA minicircles (MCs) having a fixed rotational orientation of DNA curvature, coupled with atomic-resolution modeling. Contrasting MCs with linear DNA fragments having identical sequences enabled us to analyze the impact of DNA distortion on the efficiency and selectivity of integration. We observed a global enhancement of HIV-1 integration in MCs and an enrichment of integration sites in the outward-facing DNA major grooves. Both of these changes are favored by LEDGF/p75, revealing a new, histone-independent role of this integration cofactor. PFV integration is also enhanced in MCs, but is not associated with a periodic redistribution of integration sites, thus highlighting its distinct catalytic properties. MCs help to separate the roles of target DNA structure, histone modifications and integrase (IN) cofactors during retroviral integration and to reveal IN-specific regulation mechanisms.

摘要

染色质调节逆转录病毒整合到受感染细胞基因组中的选择性。在核小体水平上，组蛋白和DNA结构都参与了这种调节。我们提出了一种策略，该策略能够专门研究单一因素：核小体诱导的DNA扭曲。此策略依赖于使用具有固定DNA曲率旋转方向的DNA微环（MCs）模拟这种扭曲，并结合原子分辨率建模。将MCs与具有相同序列的线性DNA片段进行对比，使我们能够分析DNA扭曲对整合效率和选择性的影响。我们观察到HIV-1在MCs中的整合总体增强，且整合位点在向外的DNA大沟中富集。这两种变化均受到LEDGF/p75的促进，揭示了这种整合辅因子一种新的、不依赖组蛋白的作用。PFV在MCs中的整合也增强，但与整合位点的周期性重新分布无关，从而突出了其独特的催化特性。MCs有助于在逆转录病毒整合过程中区分靶DNA结构、组蛋白修饰和整合酶（IN）辅因子的作用，并揭示IN特异性调节机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/3d69d5076f3f/gkw651fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/8e56f71a5303/gkw651fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/f10a499c9c5f/gkw651fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/31c68c3253ea/gkw651fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/476444a1612d/gkw651fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/645536674dd6/gkw651fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/8458c62a6b74/gkw651fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/3d69d5076f3f/gkw651fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/8e56f71a5303/gkw651fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/f10a499c9c5f/gkw651fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/31c68c3253ea/gkw651fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/476444a1612d/gkw651fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/645536674dd6/gkw651fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/8458c62a6b74/gkw651fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c74/5027509/3d69d5076f3f/gkw651fig7.jpg

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