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Repriming replication roadblocks

by Sanjay Mishra

Damage to DNA can stall the machinery that faithfully replicates DNA from cell to cell. Failed DNA replication can have health consequences such as cancer. An ancient primase polymerase – PrimPol – helps the replication machinery skip over common lesions and restarts DNA synthesis by “repriming” further away from roadblocks.

Now in a study published last month in Nature Communications, Aaron Ehlinger, Ph.D., Walter Chazin, Ph.D., and collaborators in England show that PrimPol is recruited to reprime DNA synthesis through its interaction with the essential single-stranded DNA binding Replication Protein A (RPA).

Using techniques that reveal protein structures in high resolution, the researchers found that PrimPol possesses two RPA-binding motifs (RBM). One of these motifs is critical for PrimPol’s recruitment to the stalled replication forks. Mutations in both RBMs have been identified in cancer patient cell lines and can affect PrimPol-RPA interactions.

These findings provide significant molecular insights into PrimPol’s role in restarting stalled replication forks.

This research was supported by grants from the National Institutes of Health (CA009582, GM116302, GM065484, GM118089).

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