Induction of a Cellular DNA Damage Response by Porcine Circovirus Type 2 Facilitates Viral Replication and Mediates Apoptotic Responses

Abstract

Cellular DNA damage response (DDR) triggered by infection of DNA viruses mediate cell cycle checkpoint activation, DNA repair, or apoptosis induction. In the present study, infection of porcine circovirus type 2 (PCV2), which serves as a major etiological agent of PCV2-associated diseases (PCVAD), was found to elicit a DNA damage response (DDR) as observed by the phosphorylation of H2AX and RPA32 following infection. The response requires active viral replication, and all the ATM (ataxia telangiectasia-mutated kinase), ATR (ATM- and Rad3-related kinase), and DNA-PK (DNA-dependent protein kinase) are the transducers of the DDR signaling events in the PCV2-infected cells as demonstrated by the phosphorylation of ATM, ATR, and DNA-PK signalings as well as reductions in their activations after treatment with specific kinase inhibitors. Inhibitions of ATM, ATR, and DNA-PK activations block viral replication and prevent apoptotic responses as observed by decreases in cleaved poly-ADP ribose polymerase (PARP) and caspase-3 as well as fragmented DNA following PCV2 infection. These results reveal that PCV2 is able to exploit the cellular DNA damage response machinery for its own efficient replication and for apoptosis induction, further extending our understanding for the molecular mechanism of PCV2 infection.

Inhibitor of Apoptosis Proteins Determines Glioblastoma Stem-Like Cell Fate in an Oxygen-Dependent Manner

“…Toledo et al proposed a tumor‐suppressive potential of ATR activation in a DNA‐damage‐independent manner by promoting cell cycle arrest . ATR activation has also been described to trigger apoptosis, and under our conditions, ATR could be involved both in proliferation arrest and apoptosis induction . Moreover, we showed that TNFα expression increased in hypoxia relative to that in normoxia and contributed to IAPs inhibition‐decreased cell viability in hypoxia as evidenced by the impaired Smac mimetic effect on cell viability caused by Enbrel.…”

Rotavirus activates a noncanonical ATM‐Chk2 branch of DNA damage response during infection to positively regulate viroplasm dynamics

“…(a) MA104 cells were either mock infected or infected with rotavirus-SA11 in the presence of DMSO, KU-55933 (10 μM), or BML-277 (10 μM), and whole cell lysates were prepared at 3 and 6 hpi. Concurrent observation of MRN-dependent ATM activation has also been reported for several viruses including MVC, MVM, HPV, PCV2, and HSV-1 Moody & Laimins, 2009;Adeyemi et al, 2010;Luo et al, 2011;Wei et al, 2016). (b, c) MA104 cells were mock infected or infected with rotavirus-SA11 in the presence of DMSO, KU-55933 (10 μM), or BML-277 (10 μM).…”

“…Averting unfavourable outcomes of such host-virus interaction has been virusinduced optimisation of DDR-a noncanonical response with multiple layers of complexity. *** p ≤ .001, unpaired t test Zhao et al, 2008;Moody & Laimins, 2009;Adeyemi et al, 2010;Luo et al, 2011;Baer et al, 2012;Wei et al, 2016). Noncanonical usurpation of DDR is how viruses ensure selective exploitation of certain DDR components while subverting others thereby mitigating untoward consequences.…”

“…The members of ATM mediated DDR pathway have been shown to be recruited at the virus replication centres within the nucleus during HSV-1, SV40, MVC, and PCV2 infection Zhao et al, 2008;Adeyemi et al, 2010;Wei et al, 2016). Indeed, subcompartmentalisation of selective DDR constituents within viral replication centres has been reported for many viruses where they colocalised with viral replication proteins.…”

“…This gives rise to the notion of virus-induced noncanonical DDR-a skewed signalling, often spatially and tempo- (Gaspar & Shenk, 2006), simian virus 40 (SV40; Dahl et al, 2005;Zhao et al, 2008), minute virus of mice (MVM; Adeyemi et al, 2010), minute virus of canine (MVC; Luo et al, 2011), and porcine circovirus Type 2 (PCV2; Wei et al, 2016) where DDR is either selectively exploited or antagonised to gain control over host cell cycle and cell-death machinery in favour of viral replication. This gives rise to the notion of virus-induced noncanonical DDR-a skewed signalling, often spatially and tempo- (Gaspar & Shenk, 2006), simian virus 40 (SV40; Dahl et al, 2005;Zhao et al, 2008), minute virus of mice (MVM; Adeyemi et al, 2010), minute virus of canine (MVC; Luo et al, 2011), and porcine circovirus Type 2 (PCV2; Wei et al, 2016) where DDR is either selectively exploited or antagonised to gain control over host cell cycle and cell-death machinery in favour of viral replication.…”