Abstract
Virus–host cell interactions include several skirmishes between the virus and its host, and the DNA damage response (DDR) network is one of their important battlegrounds. Although some aspects of the DDR are exploited by adenovirus (Ad) to improve virus replication, especially at the early phase of infection, a large body of evidence demonstrates that Ad devotes many of its proteins, including E1B-55K, E4orf3, E4orf4, E4orf6, and core protein VII, and utilizes varied mechanisms to inhibit the DDR. These findings indicate that the DDR would strongly restrict Ad replication if allowed to function efficiently. Various Ad serotypes inactivate DNA damage sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, DNA-dependent protein kinase (DNA-PK), and Poly (ADP-ribose) polymerase 1 (PARP-1). As a result, these viruses inhibit signaling via DDR transducers, such as the ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) kinases, to downstream effectors. The different Ad serotypes utilize both shared and distinct mechanisms to inhibit various branches of the DDR. The aim of this review is to understand the interactions between Ad proteins and the DDR and to appreciate how these interactions contribute to viral replication.
Highlights
Virus–host cell interactions include several skirmishes between the virus and its host, and the DNA damage response (DDR) network is one of their important battlegrounds
SLX4 was shown to promote Ad5 genome accumulation and protein production [63]; DNA-PK was shown to be activated early during infection with an Ad5 mutant lacking the whole E4 region except E4orf4, and to facilitate E4orf4-induced inactivation of ataxia-telangiectasia mutated (ATM) and ATR signaling at the early phase [62]; and ATR activation by Ad12 and hyperphosphorylation of RPA32 were suggested to contribute to inhibition of cellular DNA replication for efficient viral replication, as replication protein A (RPA) hyperphosphorylation was reported to inhibit host DNA
The results indicate that DNA-PK inhibits the temporal switch in L1 alternative RNA splicing, an effect that would be required at the early stage of infection when the
Summary
Maintaining genome integrity, both during DNA replication and following exposure to exogenous or endogenous DNA-damaging agents, is crucial for normal cell survival and prevents pathologies such as cancer [1,2]. The sensors recruit signal transducers, such as members of the phosphatidylinositol-3-kinase-like protein kinase family (PIKK), including ataxia-telangiectasia mutated (ATM), ATM- and Rad3-related (ATR), and the catalytic subunit of DNA-PK (DNA-PKcs) [3,5]. Nbs contains an ATM-binding sequence that allows recruitment of this kinase to MRN-bound damage sites to initiate ATM-mediated DNA damage signaling. End resection may lead to activation of the ATR kinase by the ssDNA (reviewed in [16]) Both ATM and ATR can transduce the MRN-generated DNA damage signal, ATM has been recognized as its main transducer. In the form of a Ku70/Ku80 heterodimer, rapidly detect DSBs and bind to the damage site within seconds These proteins keep the two ends of the broken DNA molecule together and recruit the catalytic kinase subunit, DNA-PKcs, to generate the DNA-PK holoenzyme. After the DDR has been launched, PAR chains are removed by hydrolyzing enzymes such as Poly (ADP-ribose) glycohydrolase (PARG) [30]
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