Over the last 15 years, Dr. Stillman's group has systematically uncovered many of the pre-RC and pre-IC proteins, and meticulously catalogued when and where each protein interacts with its collaborators. Having found out previously that DDK targets a multi-subunit protein complex called MCM, they've now narrowed down DDK's binding site to a domain within one of the subunits, Mcm4, where it phosphorylates a series of amino acids-protein building blocks-that otherwise inhibit Mcm4 from functioning.

The discovery of this self-inhibitory activity within Mcm4 and the finding that DDK is required to overcome it was a surprise, according to the authors. They propose that such complexity might have evolved in response to the importance of precision and accuracy of DNA replication.

"Although this is the only essential role for DDK under normal conditions, we have found that DDK takes on another task when the cell suffers DNA damage," says Dr. Stillman. In this hazardous situation, he and his colleague found, DDK activates an S-phase checkpoint mechanism that halts the DNA copying process and initiates DNA repair.

"This discovery of these distinct functions of DDK represents a key piece of the puzzle of how the initiation of DNA replication is coordinated and controlled by kinase proteins," says Dr. Stillman.

Source: Cold Spring Harbor Laboratory