An Adenovirus early region 4 deletion mutant induces G2/M arrest via ATM activation and reduces expression of the mitotic marker phosphorylated (ser10) histone 3

• Published in: Virology (New York, N.Y.) N.Y.), 2022-01, Vol.565, p.1-12
• Main Authors: Kafle, Chandra Mani, Anderson, Ashlyn Y., Prakash, Anand, Swedik, Stephanie, Bridge, Eileen
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviridae Infections - metabolism; Adenoviridae Infections - virology; Adenovirus; Adenovirus E4 Proteins - genetics; Animals; Ataxia Telangiectasia Mutated Proteins - metabolism; ATM; Cell Cycle; Cell cycle arrest; Checkpoint Kinase 1 - metabolism; Checkpoint Kinase 2 - metabolism; Chlorocebus aethiops; DNA Damage; DNA damage response; DNA Replication; DNA, Viral; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation; HeLa Cells; Histones - metabolism; Host cell shutoff; Host Microbial Interactions; Humans; Mitosis; Phosphorylation; Sequence Deletion
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2021.09.006

Adenovirus (Ad) type 5 (Ad5) early region 4 (E4) proteins inhibit the DNA damage response (DDR) including activation of the DDR kinase ATM and its substrates, which can induce G2/M cell cycle arrest. Infection with Ad5 or the E4 deletion mutant H5dl1007 (1007) resulted in the accumulation of post G1 cells with > 2 N cellular DNA content. A greater fraction of cells with 4 N DNA content was observed in 1007 infections compared to Ad5; this population was dependent on activation of ATM. G2/M checkpoint kinases, phosphorylated Chk2 (pChk2), and phosphorylated Cdk1 (pCdk1) were upregulated in 1007 infections, and 1007 showed reduced levels of the mitosis marker phosphorylated (Ser10) histone 3 compared to Ad5. Our results show that E4 mutant activation of ATM induces G2/M arrest via activation of checkpoint kinases, thereby contributing to viral-mediated regulation of the cell cycle. •Ad infection induces cellular DNA replication while preventing cell division.•E4 mutant activation of ATM and downstream G2/M checkpoint kinases results in the accumulation of infected cells in G2/M.•E4 mutant infection prevents expression of the mitosis marker phosphorylated (Ser10) histone 3.