The Role of DNA Repair Pathways in Adeno-Associated Virus Infection and Viral Genome Replication / Recombination / Integration

Abstract

Cellular DNA is constantly being damaged not only by extrinsic factors such as ionizing radiation and environmental carcinogens but also by intrinsic agents such as reactive oxygen species arising during normal cellular metabolism. Of the myriad of DNA lesions, inflicted by extrinsic and intrinsic genome damaging agents, DNA double strand break (DSB) is the most threatening. Replication fork arrest at DNA lesions could also be a threat since stalled replication forks, if fail to restart appropriately, induce DNA strand breaks. When cells encounter such strand breaks and other types of DNA damage, they mount a DNA damage response (DDR) (Harper & Elledge, 2007) that senses DNA damage and initiates a cascade of signal transduction pathways consequently culminating in cell cycle arrest, DNA repair and/or apoptosis when the DNA lesions become irreparable. Although cells are equipped with such DNA damage sensing and repair machinery primarily to handle damaged cellular DNA, triggers and receivers of DDR are not necessarily the cells' own genetic materials. DDR can also be provoked by essentially non-damaged DNA exogenously introduced into cells, most commonly viral genetic materials in nature and recombinant DNA (e.g., viral vectors for gene delivery) in laboratory. During virus-host interaction, viruses manipulate DDR upon infection of cells in a way that benefits their life cycles, while host cells fight against them to eliminate the invaders. DDR is detrimental to viral life cycles in many instances; therefore, DDR is often viewed as an innate antiviral host defense mechanism. For example, adenoviruses express viral proteins that block