Wss1 metalloprotease partners with Cdc48/Doa1 in processing genotoxic SUMO conjugates

DNA repair is essential for cell survival. Every time DNA is damaged, several protein complexes sense the damage and act to repair it. These complexes need to be carefully regulated. One way this is achieved is by the addition of molecular tags that change the activity of these complexes. Sumoylation is one such modification, which involves the addition of a bulky molecular tag called SUMO. Sumoylation during DNA damage is known to regulate the precise assembly and activity of the repair complexes. This modification is reversible and when the DNA repair is completed, the SUMO tags are removed and the repair complexes are disassembled. A protein called Cdc48 was known to work together with other molecules to clear SUMO-modified complexes from the DNA after the repair is complete. But it was unclear how this occurred and what roles other proteins played in the process. Balakirev et al. now analyze the detailed workings of another protein called Wss1 and how it contributes to SUMO processing in yeast cells. The experiments show that Wss1 helps to remove the SUMO-modified complexes from the DNA by forming a complex with Cdc48 and the Cdc48-adaptor protein Doa1. 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 (which contains most of the cell's DNA) until it senses DNA damage, which it does by recognizing damage-specific forms of DNA (such as single stranded 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 ligase—an enzyme that helps to assemble polymeric SUMO. The polymeric SUMO in turn leads to the accumulation of more Wss1 and activates its protease activity. The protease cleaves the associated proteins in the repair complex, thus helping to extract the SUMO-modified proteins from the DNA. DNA damage also results in the transfer of Wss1 into a compartment inside the cell, called a vacuole. This suggests that autophagy—a mechanism used by cells to break down damaged cellular components—is one way that proteins are removed from the nucleus. Together, Balakirev et al.'s findings reveal a previously unknown role for Wss1 and introduce us to another level of control in the DNA damage response. The next challenges will be to identify specific cellular components involved in transporting Wss1 to the vacuole and to examine whether this mechanism is conserved with a human version of Wss1, the Spartan/DVC1 protein.