Bleichert group discovers new autoinhibition mechanism of origin licensing control by cryo-EM

March 18, 2022

The Bleichert Lab recently published findings that describe a new autoinhibition process of origin licensing control in yeast. Published in Nature Communications and titled “A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6,” the paper was led by first authors Jan Marten Schmidt, a former post-doctoral researcher, and Ran Yang, a current graduate student.

Prior to DNA replication, multiple loading factors much coordinate to ensure correct helicase loading and activation and prevent re-replication. The Origin Recognition Complex (ORC) binds DNA to initiate ATP-dependent recruitment of Cdc6, Cdt1 and Mcm2-7 loading. Until now, however, the structural details of ATPase site regulation and inhibitory signaling in this process were unknown.

The Bleichert group resolved questions surrounding this question in their reporting on several structures of S. cerevisiae ORC·DNA·Cdc6 intermediates, including ARS1-bound S. cerevisiae ORC and the ternary complex with Cdc6 at sub-3 Å resolution.  They found that re-replication is prevented through Orc6, which acts to assemble an autoinhibited ORC·DNA·Cdc6 intermediate that blocks origin licensing in response to CDK phosphorylation. Employing structural and biochemical techniques, Schmidt and Ran et al. constructed a revised model for the regulation of loading of the helicase motor Mcm2-7. This work will help to further inform our understanding of DNA replication.

Congratulations to the Bleichert Lab!

By Brigitte Naughton