腺病毒 E4 突变体感染过程中，DNA-PK 在 Ser2056 的磷酸化由病毒 DNA 复制促进，且不依赖于 MRN 复合物。

DNA-PK phosphorylation at Ser2056 during adenovirus E4 mutant infection is promoted by viral DNA replication and independent of the MRN complex.

机构信息

Department of Microbiology, Miami University, Oxford, OH, USA.

Department of Microbiology, Miami University, Oxford, OH, USA; Cell Molecular and Structural Biology Program, Miami University, Oxford, OH, USA.

出版信息

Virology. 2022 Jan 2;565:82-95. doi: 10.1016/j.virol.2021.10.011. Epub 2021 Nov 2.

DOI:10.1016/j.virol.2021.10.011

PMID:34768112

Abstract

Adenovirus (Ad) early region 4 (E4) mutants activate cellular DNA damage responses (DDRs) that include non-homologous end joining (NHEJ) pathways mediated by the DNA repair kinase DNA-PK and its associated factors Ku70/Ku86. NHEJ results in concatenation of the viral linear double-stranded DNA genome and inhibits a productive infection. E4 proteins normally prevent activation of cellular DDRs in wild-type Ad type 5 (Ad5) infections, thereby promoting efficient viral growth. The purpose of this study was to evaluate the factors that govern DNA-PK activation during adenovirus infection. Our data indicate that viral DNA replication promotes DNA-PK activation, which is required for genome concatenation by NHEJ. Although the Mre11/Rad50/Nbs1 (MRN) DDR sensor complex is not required for DNA-PK activation, Mre11 is important for recruitment of the NHEJ factor Ku86 to viral replication centers. Our study addresses the interplay between the DNA-PK and MRN complexes during viral genome concatenation by NHEJ.

摘要

腺病毒（Ad）早期区域 4（E4）突变体激活细胞 DNA 损伤反应（DDR），包括由 DNA 修复激酶 DNA-PK 及其相关因子 Ku70/Ku86 介导的非同源末端连接（NHEJ）途径。NHEJ 导致病毒线性双链 DNA 基因组的串联，并抑制有效的感染。E4 蛋白通常可防止野生型 Ad 型 5（Ad5）感染中细胞 DDR 的激活，从而促进有效的病毒生长。本研究的目的是评估在腺病毒感染过程中控制 DNA-PK 激活的因素。我们的数据表明，病毒 DNA 复制促进 DNA-PK 的激活，这是 NHEJ 进行基因组串联所必需的。虽然 Mre11/Rad50/Nbs1（MRN）DDR 传感器复合物对于 DNA-PK 的激活不是必需的，但 Mre11 对于 NHEJ 因子 Ku86 招募到病毒复制中心是重要的。我们的研究解决了在 NHEJ 过程中 DNA-PK 和 MRN 复合物之间的相互作用。