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• W2969850272 abstract "Human cytomegalovirus (HCMV), like many other DNA viruses, can cause genome instability and activate a DNA damage response (DDR). Activation of ataxia-telangiectasia mutated (ATM), a kinase activated by DNA breaks, is a hallmark of the HCMV-induced DDR. Here we investigated the activation of caspase-2, an initiator caspase activated in response to DNA damage and supernumerary centrosomes. Of 7 HCMV strains tested, only strain AD169 activated caspase-2 in infected fibroblasts. Treatment with an ATM inhibitor or inactivation of PIDD or RAIDD inhibited caspase-2 activation, indicating that caspase-2 was activated by the PIDDosome. A set of chimeric HCMV strains was used to identify the genetic basis of this phenotype. Surprisingly, we found a single nucleotide polymorphism within the AD169 UL55 ORF, resulting in a D275Y amino acid exchange within glycoprotein B (gB), to be responsible for caspase-2 activation. As gB is an envelope glycoprotein required for fusion with host cell membranes, we tested whether gB(275Y) altered viral entry into fibroblasts. While entry of AD169 expressing gB(275D) proceeded slowly and could be blocked by a macropinocytosis inhibitor, entry of wild-type AD169 expressing gB(275Y) proceeded more rapidly, presumably by envelope fusion with the plasma membrane. Moreover, gB(275Y) caused the formation of syncytia with numerous centrosomes, suggesting that cell fusion triggered caspase-2 activation. These results suggest that gB variants with increased fusogenicity accelerate viral entry, cause cell fusion, and thereby compromise genome stability. They further suggest the ATM-PIDDosome-caspase-2 signaling axis alerts the cell of potentially dangerous cell fusion." @default.
• W2969850272 created "2019-08-29" @default.
• W2969850272 creator A5029006093 @default.
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• W2969850272 creator A5090360324 @default.
• W2969850272 date "2019-08-19" @default.
• W2969850272 modified "2023-10-16" @default.
• W2969850272 title "Human cytomegalovirus glycoprotein B variants affect viral entry, cell fusion, and genome stability" @default.
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• W2969850272 doi "https://doi.org/10.1073/pnas.1907447116" @default.
• W2969850272 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6731671" @default.
• W2969850272 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31427511" @default.
• W2969850272 hasPublicationYear "2019" @default.
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