Parvovirus B19 NS1 protein induces cell cycle arrest at G2-phase by activating the ATR-CDC25C-CDK1 pathway

Human parvovirus b19 (b19v) infection of primary human erythroid progenitor cells (epcs) arrests infected cells at both late s-phase and g2-phase,which contain 4n dna. b19v infection induces a dna damage response (ddr) that facilitates viral dna replication but is dispensable for cell cycle arrest at g2-phase; however,a putative c-terminal transactivation domain (tad2) within ns1 is responsible for g2-phase arrest. to fully understand the mechanism underlying b19v ns1-induced g2-phase arrest,we established two doxycycline-inducible b19v-permissive ut7/epo-s1 cell lines that express ns1 or ns1mtad2,and examined the function of the tad2 domain during g2-phase arrest. the results confirm that the ns1 tad2 domain plays a pivotal role in ns1-induced g2-phase arrest. mechanistically,ns1 transactivated cellular gene expression through the tad2 domain,which was itself responsible for atr (ataxia-telangiectasia mutated and rad3-related) activation. activated atr phosphorylated cdc25c at serine 216,which in turn inactivated the cyclin b/cdk1 complex without affecting nuclear import of the complex. importantly,we found that the atr-chk1-cdc25c-cdk1 pathway was activated during b19v infection of epcs,and that atr activation played an important role in b19v infection-induced g2-phase arrest. © 2017 xu et al.