For better or worse: crosstalk of parvovirus and host DNA damage response

Abstract

Parvoviruses are a group of non-enveloped DNA viruses that have a broad spectrum of natural infections, making them important in public health. NS1 is the largest and most complex non-structural protein in the parvovirus genome, which is indispensable in the life cycle of parvovirus and is closely related to viral replication, induction of host cell apoptosis, cycle arrest, DNA damage response (DDR), and other processes. Parvovirus activates and utilizes the DDR pathway to promote viral replication through NS1, thereby increasing pathogenicity to the host cells. Here, we review the latest progress of parvovirus in regulating host cell DDR during the parvovirus lifecycle and discuss the potential of cellular consequences of regulating the DDR pathway, targeting to provide the theoretical basis for further elucidation of the pathogenesis of parvovirus and development of new antiviral drugs.

Keywords: DNA damage response; NS1; host; parvovirus; replication.

Figure 1

The model diagram of parvovirus entry cell and nuclear import. In the first step of infection, the viral capsid binds to receptors on the cell surface, and through endocytosis mediated by grid proteins, the conformation of the capsid protein changes under acidic conditions in the inner body. Most of the infected virus particles are transported to the degrading lysosome and accumulate for degradation in the lysosome. A small number of viral particles escape from the endosome and use the cytoskeleton and motion proteins to move near the nucleus, entering the nucleus through a nuclear pore dependent manner, initiating viral DNA replication within the nucleus.

Figure 2

Schematic diagram of molecular mechanisms underlying the cell apoptosis induced by parvovirus. Once the parvovirus entry into the host cells, and causes DNA damage leading to activation of pro-apoptotic signals thereby creating oxidative stress, endoplasmic reticulum stress. This cellular stress causes a decrease in mitochondrial membrane permeability, the release of cytochrome C which further forms apoptosome complex with Apaf1, activating caspase 9, finally inducing cell death by intrinsic/mitochondrial pathway.

Figure 3

Overview of the DDR pathways. DDR, DNA damage response. ATM is usually located in the nucleus as a dimer (non-activated), and the activated ATM exists as a monomer. Upon sensing the DSB signal, the heterotrimer MRE11-RAD5-NBS1 (MRN) complex binds to the double-stranded DNA (dsDNA) terminal, prompting ATM and DSB sites to interact, resulting in ATM phosphorylation, then a large number of substates CHK2, p53 were activated and inhibiting CDK2 activity, the G1/S or G2/M cell cycle is arrested. ATR is activated in response mainly related to ssDNA. When there is DNA replication stress or DNA damage in the cell, the replication-associated protein A (111) wraps single-stranded DNA (ssDNA) and forms the RPA-ssDNA complex lead to ATR activation, ATR activation may lead to the activation CHK1, SMC-1, ATM and p21, which can regulate CDC25A, RAD51, p53 and DNA-PKCs, and is crucial for two important checkpoints in G1/S phase and G2/M phase. DNA-PK is activated usually in response to DSBs. In the DNA-PK complex, Ku70/Ku80 proteins endows the DSB terminal with high affinity and acts as an early sensor. Subsequently, DNA-PKcs was recruited into DSBs through Ku70/Ku80 proteins and triggering the activation of DNA-PKcs. After activation, DNA-PKcs recruit some host factors DNA Pol, XRCC4, PAXX and XLF to complete double stranded DNA repair.

Figure 4

The interaction of parvovirus NS1 and host DNA damage response. DDR, DNA damage response. The NS1 of MVM induced DDR depends on signal transduction by ATM kinase and leads to ATR-mediated signal inactivation, targeted RPA 32 and MRE11 expression promote viral replication. After B19V or AAV infection, three major PI3K cascades are activated of NS1, resulting in the recruitment of Ku70, ATM and ATR to the viral DNA replication center and co-localization of DNA damage site. HBoV infection of human respiratory epithelial cells cultured at the gas-liquid interface can induce significant DDR, and Ku70 activation has been shown to be a key DDR pathway for HBoV DNA replication.