Human cytomegalovirus (HCMV) inactivates a DNA damage response by booting two checkpoint proteins out of the nucleus, according to Miguel Gaspar and Thomas Shenk (Princeton University, Princeton, NJ).
When DNA herpesviruses like HCMV replicate, the double-stranded ends of their genomes, which resemble breaks, can trigger a cell's DNA damage checkpoint pathway. Viruses have evolved several mechanisms to inactivate the checkpoint and proceed with replication, such as degrading an essential checkpoint component or using the block in cell cycle progression to their advantage.
Gaspar and Shenk now show that HCMV thwarts the checkpoint in a novel way—by trapping two essential checkpoint proteins, ATM and Chk2, in the cytoplasm. “This is the first time a virus has been found to antagonize a DNA damage checkpoint by mislocalization,” notes Shenk.
The checkpoint proteins wind up hanging out with viral proteins in the cytoplasmic “virion assembly zone.” Whether ATM and Chk2 get ferried out of the nucleus by the viral proteins or another viral protein blocks the checkpoint proteins' normal nuclear import remains to be answered.
Shenk says the HCMV studies could shed light on the poorly defined nuclear import mechanism—following his motto: “If a virus goes after it, it's probably important.”