SMC1-mediated intra-S-phase arrest facilitates bocavirus DNA replication.
Activation of a host DNA damage response (DDR) is essential for DNA replication of minute virus of canines (MVC), a member of the genus Bocavirus of the Parvoviridae family; however, the mechanism by which DDR contributes to viral DNA replication is unknown. In the current study, we demonstrate that MVC infection triggers the intra-S-phase arrest to slow down host cellular DNA replication and to recruit cellular DNA replication factors for viral DNA replication. The intra-S-phase arrest is regulated by ATM (ataxia telangiectasia-mutated kinase) signaling in a p53-independent manner. Moreover, we demonstrate that SMC1 (structural maintenance of chromosomes 1) is the key regulator of the intra-S-phase arrest induced during infection. Either knockdown of SMC1 or complementation with a dominant negative SMC1 mutant blocks both the intra-S-phase arrest and viral DNA replication. Finally, we show that the intra-S-phase arrest induced during MVC infection was caused neither by damaged host cellular DNA nor by viral proteins but by replicating viral genomes physically associated with the DNA damage sensor, the Mre11-Rad50-Nbs1 (MRN) complex. In conclusion, the feedback loop between MVC DNA replication and the intra-S-phase arrest is mediated by ATM-SMC1 signaling and plays a critical role in MVC DNA replication. Thus, our findings unravel the mechanism underlying DDR signaling-facilitated MVC DNA replication and demonstrate a novel strategy of DNA virus-host interaction.
Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Yong
Y
Luo
Xuefeng
X
Deng
Fang
F
Cheng
Yi
Y
Li
Jianming
J
Qiu
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015139:Blotting, Southern; D052660:Bocavirus / Q000235:genetics*; D001973:Bromodeoxyuridine; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology*; D020552:Comet Assay; D004261:DNA Replication / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004285:Dogs; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D054884:Host-Pathogen Interactions; D015151:Immunoblotting; D010322:Parvoviridae Infections / Q000503:physiopathology*; D010957:Plasmids / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D059807:S Phase Cell Cycle Checkpoints / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000098550:Structural Maintenance of Chromosome Protein 1
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D000098550:Structural Maintenance of Chromosome Protein 1; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D001973:Bromodeoxyuridine