The new study, which was published on April 12, 2009, in an advanced online edition of the journal Nature Structural & Molecular Biology, draws new parallels between the Rad60 DNA repair factor and SUMO, a small ubiquitin-like modifier, which are both essential for maintaining genome stability during replication.
"This collaborative study between our laboratory and the Scripps Research Tainer group shows the very first indication of mimicry in the SUMO pathway," said Scripps Research Assistant Professor Michael "Nick" Boddy, Ph.D., who was senior author of the study. "By mimicking a particular surface feature of SUMO, Rad60 competes for binding to an essential enzyme of the SUMO machinery. Thus, Rad60 is a previously undefined member of the SUMO team."
Maintaining genome stability is critical to an organism's survival because genetic defects can promote tumors, aging, and neurodegenerative disease. The genome is particularly vulnerable to spontaneous and damage induced alterations during the replication or S phase of cell division. To ensure the high-fidelity completion of replication, cells engage critical mechanisms that include cell cycle checkpoints and DNA repair.
The fission yeast (Schizosaccharomyces pombe) DNA repair protein Rad60, part of a unique protein family conserved from yeast to humans, is essential for cell viability; cells with a reduced level of Rad60 activity show sensitivity to a range of genotoxic stresses.
The new study combined structural, biochemical and genetic analyses in the two laboratories. The results showed that the two SUMO-like domains on Rad60 each bind to distinct components of the SUMO pathway.
"Even though the backbones in these two Rad60 domains are similar, their surfaces have been altered during evolution in such a way to maintain interaction with different parts of the SUMO pathway," said Boddy, who just received a prestigious Scholar Award from the Leukemia & Lymphoma Society, and who, with colleagues, first identified the Rad60 family in 2003 and was among the first to characterize SUMO in 1996.