Mechanism of a DNA repair protein

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A DNA replication machine acts at a “replication fork” to unzip and copy DNA. But many obstacles, such as damaged DNA and unusual DNA structures, can stall replication forks with severe consequences, such as mutation and DNA rearrangements that cause cancer.

Replication stress response proteins such as ZRANB3 minimize inaccuracies in DNA copying by stabilizing and restarting stalled replication forks.

Now, in a paper published in The Journal of Biological ChemistryDavid Cortez, Ph.D., Brandt Eichman, Ph.D., and colleagues identify a critical substrate recognition domain (SRD) in ZRANB3 that recognizes and actively remodels the DNA fork.

They showed that without SRD, ZRANB3 fails to bind the fork DNA. The SRD fragment itself is sufficient to impart DNA binding and activate the fork remodeling activity of the ZRANB3 motor. They also demonstrate that SRD is required for the structure-specific DNA cutting activity of ZRANB3.

These discoveries reveal the mechanism of this important DNA repair protein that maintains genome stability.

This work was supported by National Institutes of Health grants CA102729, CA092584 and CA102729.