Intasome architecture and chromatin density modulate retroviral integration into nucleosome.
Intasome architecture and chromatin density modulate retroviral integration into nucleosome.
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DOI：
10.1186/s12977-015-0145-9
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发表时间：
2015-02-07
期刊：
影响因子：
3.3
通讯作者：
Parissi V
中科院分区：
文献类型：
--
作者：
Benleulmi MS;Matysiak J;Henriquez DR;Vaillant C;Lesbats P;Calmels C;Naughtin M;Leon O;Skalka AM;Ruff M;Lavigne M;Andreola ML;Parissi V
逆转录病毒整合依赖于整合体、宿主染色质和细胞靶向辅因子如LEDGF/p75或BET蛋白之间的相互作用。先前的研究表明，逆转录病毒整合酶本身可能在核小体靶DNA内的局部整合位点选择中发挥作用。我们通过分析各种逆转录病毒整合体的内在特性，在缺乏其他辅因子的情况下，在功能上适应不同的染色质结构，将我们的研究集中在这种局部关联上。使用在体外条件下，允许有效的催化没有这些辅因子的全站点整合，我们表明，不同的逆转录病毒整合酶是不一样的染色质致密性的影响。事实上，虽然PFV和MLV整合反应有利于进入致密和稳定的核小体，但HIV-1和ASV协同整合反应优选进入我们的核小体受体模板的低密度染色质区域。在感染细胞中鉴定的整合位点周围预测的核小体占据表明，MLV和HIV-1整合位点处存在核小体，并被不同密度的染色质包围。体外整合位点的选择性和插入的DNA的结构之间的关系的进一步分析表明，intasome内的结构约束可以解释它们的能力，以适应核小体DNA，并可以决定它们的能力，结合核小体功能在这些特定的染色质背景。因此，整合体结构和紧密性的染色质周围的靶向核小体出现的逆转录病毒整合位点的选择性的重要决定因素。这支持了一种机制，该机制涉及整合体向合适的染色质区域的全局靶向，随后是由整合体的内在结构约束调节的局部整合位点选择，该内在结构约束支配靶DNA弯曲并指示它们对合适的特定核小体结构和密度的敏感性。本文的在线版本（doi：10.1186/s12977-015-0145-9）包含补充材料，可供授权用户使用。
Retroviral integration depends on the interaction between intasomes, host chromatin and cellular targeting cofactors as LEDGF/p75 or BET proteins. Previous studies indicated that the retroviral integrase, by itself, may play a role in the local integration site selection within nucleosomal target DNA. We focused our study on this local association by analyzing the intrinsic properties of various retroviral intasomes to functionally accommodate different chromatin structures in the lack of other cofactors. Using in vitro conditions allowing the efficient catalysis of full site integration without these cofactors, we show that distinct retroviral integrases are not equally affected by chromatin compactness. Indeed, while PFV and MLV integration reactions are favored into dense and stable nucleosomes, HIV-1 and ASV concerted integration reactions are preferred into poorly dense chromatin regions of our nucleosomal acceptor templates. Predicted nucleosome occupancy around integration sites identified in infected cells suggests the presence of a nucleosome at the MLV and HIV-1 integration sites surrounded by differently dense chromatin. Further analyses of the relationships between the in vitro integration site selectivity and the structure of the inserted DNA indicate that structural constraints within intasomes could account for their ability to accommodate nucleosomal DNA and could dictate their capability to bind nucleosomes functionally in these specific chromatin contexts. Thus, both intasome architecture and compactness of the chromatin surrounding the targeted nucleosome appear important determinants of the retroviral integration site selectivity. This supports a mechanism involving a global targeting of the intasomes toward suitable chromatin regions followed by a local integration site selection modulated by the intrinsic structural constraints of the intasomes governing the target DNA bending and dictating their sensitivity toward suitable specific nucleosomal structures and density. The online version of this article (doi:10.1186/s12977-015-0145-9) contains supplementary material, which is available to authorized users.
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影响因子：
6.7
作者：
Hare S;Shun MC;Gupta SS;Valkov E;Engelman A;Cherepanov P
通讯作者：
Cherepanov P
影响因子：
11.4
作者：
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通讯作者：
Cherepanov, Peter
影响因子：
6.7
作者：
Engelman A;Cherepanov P
通讯作者：
Cherepanov P
影响因子：
10.5
作者：
BOWERMAN, B;BROWN, PO;VARMUS, HE
通讯作者：
VARMUS, HE
DOI：
10.1073/pnas.1216254110
发表时间：
2013-04-02
影响因子：
11.1
作者：
Di Primio, Cristina;Quercioli, Valentina;Cereseto, Anna
通讯作者：
Cereseto, Anna