Host nuclear DNA repair and replication machinery acting on Adeno-associated virus (AAV) genome (AAV-DDR/Replication Machinery)

The host nuclear DNA repair and replication machinery acting on the AAV genome encompasses the suite of cellular proteins recruited to the Adeno-associated virus (AAV) genome following its nuclear entry. Because AAV is a single-stranded DNA (ssDNA) virus, it relies entirely on the host's replication and repair apparatus to convert its genome into a double-stranded DNA (dsDNA) template. This process, known as second-strand synthesis, is the primary rate-limiting step for transgene expression in AAV-mediated gene therapy (Ferrari et al., 1996). Key players include DNA polymerases delta and epsilon, replication protein A (RPA), and various DNA damage response (DDR) proteins like the Mre11-Rad50-Nbs1 (MRN) complex and ATM/ATR kinases (Nash et al., 2008; Choi et al., 2006). These host factors recognize the viral inverted terminal repeats (ITRs) as damaged DNA, triggering a response that determines the fate of the viral genome. The machinery facilitates the formation of stable, transcriptionally active episomal concatemers or, less frequently, the integration of the viral DNA into the host genome (Weitzman & Linden, 2011). Pharmacological agents such as hydroxyurea or topoisomerase inhibitors can modulate these host factors to enhance vector efficiency by inducing a pseudo-S-phase or DNA damage signaling (Russell et al., 1995). However, manipulating these fundamental cellular pathways carries significant risks, including potential genotoxicity and unintended alterations to the host's genomic stability.

Other names

AAV host cell factorsAAV second-strand synthesis machineryAAV-DDR interfaceHost DNA damage response factors

Modulation of host DNA damage response and replication pathways to facilitate the conversion of single-stranded AAV DNA into double-stranded episomes or to influence genome integration.