Activation of the DNA Damage Response by RNA Viruses

Abstract

RNA viruses are a genetically diverse group of pathogens that are responsible for some of the most prevalent and lethal human diseases. Numerous viruses introduce DNA damage and genetic instability in host cells during their lifecycles and some species also manipulate components of the DNA damage response (DDR), a complex and sophisticated series of cellular pathways that have evolved to detect and repair DNA lesions. Activation and manipulation of the DDR by DNA viruses has been extensively studied. It is apparent, however, that many RNA viruses can also induce significant DNA damage, even in cases where viral replication takes place exclusively in the cytoplasm. DNA damage can contribute to the pathogenesis of RNA viruses through the triggering of apoptosis, stimulation of inflammatory immune responses and the introduction of deleterious mutations that can increase the risk of tumorigenesis. In addition, activation of DDR pathways can contribute positively to replication of viral RNA genomes. Elucidation of the interactions between RNA viruses and the DDR has provided important insights into modulation of host cell functions by these pathogens. This review summarises the current literature regarding activation and manipulation of the DDR by several medically important RNA viruses.

Keywords: DNA damage response; HCV; HIV-1; HTLV-1; IBV; Influenza A; RNA viruses; retroviruses.

Figure 1

ATM, ATR and DNA-PK signalling pathways. The DNA damage signalling pathways are primarily mediated by the ATM, ATR and DNA-PK kinases. DSBs are detected by the MRN complex (MRE11, RAD50 and NBS1) which recruits and activates ATM at the site of the break. Activated ATM phosphorylates numerous effector proteins such as CHK2 and p53. Phosphorylation of the histone variant H2AX by ATM and ubiquitination of H2AX by RNF8 and RNF168 E3 ubiquitin ligases precedes recruitment of repair proteins such as BRCA1 and 53BP1. ATR is primarily activated at regions of ssDNA which are first coated by RPA. ATR is then recruited to RPA-coated ssDNA via its interacting protein ATRIP. The recruitment of TOPBP1 to the ssDNA region is responsible for the activation of ATR which subsequently phosphorylates effector proteins such as CHK1 and p53. In contrast to the ATM and ATR kinases, DNA-PK is responsible for the regulation of the NHEJ DSB repair pathway. Image adapted from [15].

Figure 2

The basic steps in the retroviral integration process. 1. Viral integrase (IN) processes the viral DNA ends. 2. IN then catalyses the cleavage of host DNA and attachment of viral DNA forming an integration intermediate. 3. Finally, host factors repair the single strand gaps resulting in a stably integrated provirus. Image adapted from [120]. (2003) National Academy of Sciences, USA.