Modulation of DNA damage and repair pathways by human tumour viruses

Abstract

With between 10% and 15% of human cancers attributable to viral infection, there is great interest, from both a scientific and clinical viewpoint, as to how these pathogens modulate host cell functions. Seven human tumour viruses have been identified as being involved in the development of specific malignancies. It has long been known that the introduction of chromosomal aberrations is a common feature of viral infections. Intensive research over the past two decades has subsequently revealed that viruses specifically interact with cellular mechanisms responsible for the recognition and repair of DNA lesions, collectively known as the DNA damage response (DDR). These interactions can involve activation and deactivation of individual DDR pathways as well as the recruitment of specific proteins to sites of viral replication. Since the DDR has evolved to protect the genome from the accumulation of deleterious mutations, deregulation is inevitably associated with an increased risk of tumour formation. This review summarises the current literature regarding the complex relationship between known human tumour viruses and the DDR and aims to shed light on how these interactions can contribute to genomic instability and ultimately the development of human cancers.

Keywords: DNA damage; DNA repair; EBV; HBV; HCV; HPV; HTLV-1; KSHV; MCPyV; human tumour viruses.

Figure 1

ATM activation in response to DSBs. The MRN complex rapidly migrates to sites of DSBs and, along with the acetyltransferase Tip60, contributes to activation of ATM kinase activity. Phosphorylation of histone H2AX by ATM results in binding of MDC1 which subsequently mediates recruitment of factors, such as 53BP1 and BRCA1, which participate in DSB repair and regulation of cell cycle checkpoints.

Figure 2

ATR activation in response to stalled replication forks. ATR and ATRIP bind to stretches of ssDNA coated with RPA while the Rad17-RFC complex independently loads the 9-1-1 checkpoint clamp onto ssDNA/dsDNA junctions. Subsequent recruitment of TOPBP1 mediates activation of ATR while Claspin and the Timeless (Tim)/Tipin complex facilitate CHK1 activation.

Figure 3

Regulation of the cell cycle by cyclins and CDKs. In response to DNA damage phosphorylation of CHK1 and CHK2 can lead to degradation of Cdc25 phosphatases. Cdc25 degradation inhibits activation of CDKs and delays progression of the cell cycle. Increased expression of p21 by p53 following DNA damage can also mediate cell cycle arrest through inhibition of CDKs.

Figure 4

Non-homologous end joining repair of DSBs. Ku70/80 binds to DNA ends and provides a scaffold for the recruitment of additional proteins such as DNA-PKcs. If required, DNA ends may be cleaved by the Artemis nuclease and gaps filled by DNA polymerases. Finally, the ligation complex consisting of XLF, XRCC4 and DNA Ligase IV ligates the DNA ends to complete the repair.

Figure 5

Homologous recombination repair of DBSs. DNA end resection results in ssDNA that is first coated by RPA. Rad51, in conjunction with Rad52 and BRCA2, then displaces RPA. Rad51 and Rad54 catalyse strand invasion and homology search with the undamaged template. Following DNA synthesis via polymerases, the resulting Holliday junctions are resolved.