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Bromo- and extraterminal domain chromatin regulators serve as cofactors for murine leukemia virus integration.
Journal of Virology ( IF 5.4 ) Pub Date : 2013-09-18 , DOI: 10.1128/jvi.01942-13
Saumya Shree Gupta 1 , Tobias Maetzig , Goedele N Maertens , Azar Sharif , Michael Rothe , Magdalena Weidner-Glunde , Melanie Galla , Axel Schambach , Peter Cherepanov , Thomas F Schulz
Affiliation  

Retroviral integrase (IN) proteins catalyze the permanent integration of proviral genomes into host DNA with the help of cellular cofactors. Lens epithelium-derived growth factor (LEDGF) is a cofactor for lentiviruses, including human immunodeficiency virus type 1 (HIV-1), and targets lentiviral integration toward active transcription units in the host genome. In contrast to lentiviruses, murine leukemia virus (MLV), a gammaretrovirus, tends to integrate near transcription start sites. Here, we show that the bromodomain and extraterminal domain (BET) proteins BRD2, BRD3, and BRD4 interact with gammaretroviral INs and stimulate the catalytic activity of MLV IN in vitro. We mapped the interaction site to a characteristic structural feature within the BET protein extraterminal (ET) domain and to three amino acids in MLV IN. The ET domains of different BET proteins stimulate MLV integration in vitro and, in the case of BRD2, also in vivo. Furthermore, two small-molecule BET inhibitors, JQ1 and I-BET, decrease MLV integration and shift it away from transcription start sites. Our data suggest that BET proteins might act as chromatin-bound acceptors for the MLV preintegration complex. These results could pave a way to redirecting MLV DNA integration as a basis for creating safer retroviral vectors.

中文翻译:

溴和末端外域染色质调节因子作为鼠白血病病毒整合的辅助因子。

逆转录病毒整合酶 (IN) 蛋白在细胞辅助因子的帮助下催化原病毒基因组永久整合到宿主 DNA 中。晶状体上皮衍生生长因子 (LEDGF) 是慢病毒的辅助因子,包括 1 型人类免疫缺陷病毒 (HIV-1),其目标是将慢病毒整合到宿主基因组中的活性转录单位。与慢病毒相反,鼠白血病病毒 (MLV),一种伽马逆转录病毒,倾向于在转录起始位点附近整合。在这里,我们展示了溴结构域和末端结构域 (BET) 蛋白 BRD2、BRD3 和 BRD4 与 gammaretroviral IN 相互作用并在体外刺激 MLV IN 的催化活性。我们将相互作用位点映射到 BET 蛋白末端 (ET) 域内的特征结构特征和 MLV IN 中的三个氨基酸。不同 BET 蛋白的 ET 结构域在体外刺激 MLV 整合,在 BRD2 的情况下,也在体内刺激。此外,两种小分子 BET 抑制剂 JQ1 和 I-BET 会降低 MLV 整合并将其从转录起始位点转移。我们的数据表明 BET 蛋白可能充当 MLV 预整合复合物的染色质结合受体。这些结果可以为重新定向 MLV DNA 整合铺平道路,作为创建更安全的逆转录病毒载体的基础。
更新日期:2019-11-01
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