DNA-damage response pathways triggered by viral replication

Abstract

Many viruses, with distinct replication strategies, activate DNA-damage response pathways, including the lentivirus human immunodeficiency virus (HIV) and the DNA viruses Epstein-Barr virus (EBV), herpes simplex virus 1, adenovirus and SV40. DNA-damage response pathways involving DNA-dependent protein kinase, ataxia-telengiectasia mutated (ATM) and 'ataxia-telengiectasia and Rad3-related' (ATR) have all been implicated. This review focuses on the effects of HIV and EBV replication on DNA repair pathways. It has been suggested that activation of cellular DNA repair and recombination enzymes is beneficial for viral replication, as illustrated by the ability of suppressors of the ATM and ATR family to inhibit HIV replication. However, activation of DNA-damage response pathways can also promote apoptosis. Viruses can tailor the cellular response by suppressing downstream signalling from DNA-damage sensors, as exemplified by EBV. New small-molecule inhibitors of the DNA-damage response pathways could therefore be of value to treat viral infections.

Figure 1. Overview of the transition of the retroviral genome from ss RNA to integrated ds DNA

Retroviral virions contain a single-stranded (ss) RNA version of their genome. Upon infection of permissive cells, the ss RNA is converted to double-stranded (ds) DNA by the action of the virion enzyme reverse transcriptase. Reverse transcriptase employs a tRNA molecule bound near the U5 region of the ss RNA genome as an initial primer to synthesise a short region of single-stranded viral DNA, containing U5 and R regions. The DNA then dissociates from the genome and anneals to another copy of the R region, at the 3′ end of the genome. DNA synthesis proceeds along the genome to generate the negative strand. The positive strand is replicated from this template by a mechanism that uses DNA as its template and might involve circularised molecules. The RNA primer is destroyed by the RNAse H activity of reverse transcriptase. The double-stranded DNA genome is then recognised by a second virion enzyme, integrase, which cleaves two nucleotides from the 3′ end of each DNA strand at the long terminal repeat (LTR) and mediates their ligation into the host DNA. This process leaves the 5′ ends of the viral DNA unligated, resulting in single-strand breaks (SSBs).

Figure 2. Overview of lytic replication of the Epstein–Barr virus genome

Epstein–Barr virus (EBV) virions contain a double-stranded linear DNA genome. Upon infection of permissive cells, the double-stranded linear DNA is converted to circular double-stranded DNA by association of the terminal repeats (TRs). This episome form of the genome replicates once per cell division in latently infected cells (not shown), using the origin of replication OriP. Following the binding of the lytic switch transactivator Zta to the alternative replication origin OriLyt, a rolling-circle replication occurs, generating multiple copies of the linear genome. In the figure, new DNA synthesis is shown by the grey arrows. The new DNA is cut at each TR, releasing single genome-length units, which are packaged and released from the cell.