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Clipping Control

When a strand of DNA in a yeast cell breaks, one of the first responders is the endonuclease Sae2. The enzyme’s job is to trim a little from the damaged ends of the DNA in preparation for repair. But if Sae2 lingers around too long, it might end up clipping some perfectly good DNA as well. HHMI Investigator Tanya Paull of the University of Texas at Austin has figured out how cells keep the enzyme in check.

Paull’s team discovered that Sae2 normally forms nonfunctional, insoluble protein aggregates in the cell. But after DNA damage occurs, an enzyme called cyclin-dependent kinase adds several phosphate molecules to Sae2. This causes the protein clusters to break apart, and the now-soluble single molecules of Sae2 become active. The DNA damage also triggers the degradation of Sae2, ensuring the cellular “clipper” is only transiently available. The findings were published March 2014 in Molecular and Cellular Biology.

“Sae2 is an endonuclease that is potentially very toxic to cells when unregulated,” explains Paull. “So this strategy is ideal for sequestering the protein into a form that is not toxic, yet is available for immediate activation through phosphorylation.”

Paull recently discovered that CtIP—the human version of Sae2—is an endonuclease with even more phosphorylation than Sae2. The results, published in the June 19, 2014, issue of Molecular Cell, have prompted her to investigate if CtIP is also regulated by changes in solubility.