Human cytomegalovirus inhibits a DNA damage response by mislocalizing checkpoint proteins.
The DNA damage checkpoint pathway responds to DNA damage and induces a cell cycle arrest to allow time for DNA repair. Several viruses are known to activate or modulate this cellular response. Here we show that the ataxia-telangiectasia mutated checkpoint pathway, which responds to double-strand breaks in DNA, is activated in response to human cytomegalovirus DNA replication. However, this activation does not propagate through the pathway; it is blocked at the level of the effector kinase, checkpoint kinase 2 (Chk2). Late after infection, several checkpoint proteins, including ataxia-telangiectasia mutated and Chk2, are mislocalized to a cytoplasmic virus assembly zone, where they are colocalized with virion structural proteins. This colocalization was confirmed by immunoprecipitation of virion proteins with an antibody that recognizes Chk2. Virus replication was resistant to ionizing radiation, which causes double-strand breaks in DNA. We propose that human CMV DNA replication activates the checkpoint response to DNA double-strand breaks, and the virus responds by altering the localization of checkpoint proteins to the cytoplasm and thereby inhibiting the signaling pathway.
Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014, USA.
Miguel
M
Gaspar
Thomas
T
Shenk
D036022:Capsid Proteins / Q000032:analysis / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000378:metabolism; D064447:Checkpoint Kinase 2; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D003586:Cytomegalovirus Infections / Q000378:metabolism / Q000821:virology*; D003593:Cytoplasm / Q000737:chemistry* / Q000821:virology*; D004249:DNA Damage; D004261:DNA Replication; D004279:DNA, Viral / Q000378:metabolism; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000032:analysis* / Q000378:metabolism; D014466:Ultraviolet Rays; D014779:Virus Replication / Q000528:radiation effects; D020687:cdc25 Phosphatases / Q000378:metabolism
D036022:Capsid Proteins; D018797:Cell Cycle Proteins; D004279:DNA, Viral; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases