Human cytomegalovirus inhibits a DNA damage response by mislocalizing checkpoint proteins

Miguel Gaspar, Thomas Shenk

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2821-2826
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number8
DOIs
StatePublished - Feb 21 2006

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Ataxia-telangiectasia mutated pathway
  • Ionizing radiation

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