Amit Koul, Univeristy of Manitoba

Amit Koul, Lauren Fulham, Nikolas Akkerman, Drayson Graves, Esha Kaul, Khadija Khadija and Peter Pelka

Suppressing & Conquering

Human adenoviruses extensively rely on reprogramming of host transcriptional and DNA damage response (DDR) pathways to establish productive infection. E1A is the first protein produced during adenovirus infection. Via protein-protein interactions, E1A modifies the cellular environment to create optimal conditions for viral replication. To better understand the molecular mechanisms driving viral infection, we further investigated the functional consequences of the interaction between ARGLU1 and E1A. ARGLU1 interacts with E1A directly as determined by a GST-pulldown assay with recombinant proteins. Importantly, ARGLU1 was found to act as a transcriptional repressor when it was localized to viral promoters. Repression was driven by enhanced promoter-proximal RNA polymerase II pausing. Significantly, ARGLU1-induced repression of viral promoters is likely an unintended consequence of ARGLU1 binding to E1A, as a mutant of E1A (dl1102), unable to bind to ARGLU1, did not show reduced viral gene expression. Furthermore, ARGLU1 was found to colocalize with E1A in infected cell nuclei. Finally, the binding of E1A to ARGLU1 appears to reduce DNA damage repair in bleomycin-treated and adenovirus-infected cells, suggesting that E1A binding to ARGLU1 is important for DNA damage response inhibition. Overall, our study underscores the complexity of virus-host interactions and reveals a novel role for ARGLU1 during adenoviral infection.