UCLA

Diverse viruses modulate the host DNA damage response (DDR) to enhance viral replication or evade innate immune surveillance. Among primate lentiviruses, the conserved and essential accessory gene Vpr engages the DDR at multiple, potentially unique steps: Vpr induces DNA damage, activates and represses the DDR, and causes cell cycle arrest at the G2/M checkpoint. Of the three major DDR signaling kinases, DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM), and ataxia telangiectasia and Rad3 (ATR), Vpr activates ATM and ATR. The precise nature of this activation remains unclear, however, as do the downstream pathways triggered as a consequence. In this dissertation, I investigate Vpr-mediated ATM and ATR signaling and explore how each might remodel the cell in favor of lentiviral replication. In Chapter 2, I determine that Vpr activates canonical ATM signaling and triggers ATM-NEMO dependent NF-KB/ RelA transcription to remodel the host transcriptome. In Chapter 3, I determine that Vpr-induced ATR activation causes a novel phenotype, nucleolar stress, and characterize the Vpr host target CCDC137 as an important nucleolar stress sensor. Overall, this work encompasses many foundational discoveries that will have important implications for diverse fields, including HIV, nucleolar stress, genome integrity and cancer biology.