The DNA in our cells is constantly being damaged by heat, radiation and other environmental stresses, andÂ the enzyme systems that repair DNA are critical for life. A particularly toxic form of damage is the covalent attachment of a protein to DNA, which can be triggered by radiation or by anticancer drugs.
Emory biochemist Keith Wilkinson and colleagues have a paper this week in the journal eLife probing how a yeast protein called Wss1 is involved in repairing DNA-protein crosslinks. The researchers show how Wss1 wrestles with a protein tag called SUMO onÂ the site of the DNA damage, and how Wss1 and SUMO areÂ involved in the cleanup process.
Three interesting things about this paper:
*The paper grew out of first author Maxim Balakirevâ€™s sabbatical with Wilkinson at Emory. Balakirev’s home base is at the CEA (Alternative Energy and Atomic Energy Commission)Â in Grenoble, France.
* Since manyÂ cancer chemotherapy drugs induce protein-DNA cross links, an inhibitor of cross linkÂ repair could enhance those drugs’ effectiveness. On the other side of the coin, mutations in a human gene called Spartan, whose sequence looks similar to Wss1â€™s, cause premature aging and susceptibility to liver cancer. Whether the Spartan-encoded protein has the same biochemical activity as Wss1 is not yet clear.
*SUMOÂ stands for â€œsmall ubiquitin-like modifierâ€. The eLife digest has an elegant explanation of whatâ€™s happening:
Wss1 is a protease, an enzyme that can break down proteins, but it is inactive under the normal conditions inside a cell. Wss1 is found in the cell’s nucleus until it senses DNA damage, which it does by recognizing damage-specific forms of DNA and the SUMO tag.
Balakirev et al. found that Wss1 binds to the site of DNA damage and lengthens the SUMO tag. This indicates that Wss1 can also act as a ligaseâ€”an enzyme that helps to assemble polymeric SUMOâ€¦ The protease cleaves the associated proteins in the repair complex, thus helping to extract the SUMO-modified proteins from the DNA.
The 2014 Cell paper identifying Wss1â€™s function in DNA repair mentions the connection to SUMO, and Wss1’s genetic relationship to SUMO is stated in its name (Weak Suppressor of SUMO-1). However, showing that Wss1 is a SUMO ligase is new.