The SUMO pathway parallels the classical ubiquitinylation pathway with three 
discrete steps: activation involving the enzyme E1, conjugation involving the E2 
enzyme UBC9, and substrate modification through the cooperative association of 
UBC9 and E3 ligases. We report here that the adenoviral protein Gam1 inhibits 
the SUMO pathway by interfering with the activity of E1 (SAE1/SAE2). In vivo, 
Gam1 expression leads to SAE1/SAE2 inactivation, both SAE1/SAE2 and UBC9 
disappearance, and overall inhibition of protein sumoylation. This results in 
transcriptional activation of some promoters and is directly linked to 
inhibition of sumoylation of the transcriptional activators involved. Our 
results identify a mechanism for interfering with the SUMO pathway and with 
transcription that could have an impact in the design of novel pharmaceutical 
agents. They also point out once again to the extraordinary ability of 
eukaryotic viruses to interfere with the biology of host cells by targeting 
fundamental biochemical processes.