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Tolerating replication stress

By Emily Overway

Headshot of Kavi Mehta. He is wearing a dark t-shirt and eyeglasses. Kavi has a beard and mustache.
Kavi Mehta (Cortez lab)

The lab of David Cortez, Richard N. Armstrong, Ph.D. Professor of Innovation in Biochemistry and chair of the Department of Biochemistry, researches the regulation of genomic DNA replication. Recent work, “CHK1 phosphorylates PRIMPOL to promote replication stress tolerance,” was published in Science Advances in March. This research, led by first author Kavi Mehta, a postdoctoral fellow in the Cortez lab, looked at the role of CHK1, which regulates the DNA damage response and the cell cycle checkpoint response, in restarting replication after DNA damage occurs.

What issue/problem does your research address?
The imperative of the cell is to finish DNA replication. DNA damage can occur during and after this process, resulting in sites of damage called DNA lesions. Cells experience tens of thousands of DNA lesions per day that must be repaired to ensure that genetic stability is maintained. These lesions can be caused by endogenous or exogenous sources, such as replication errors or chemical agents, respectively. The replication stress response is required to repair these lesions.

Chronic genotoxic stress caused by chemical agents, genomic instability, and aberrant replication stress responses are hallmarks of cancers. Our recent paper focuses on understanding the mechanisms by which cells protect the genome from genotoxic insult and the regulation of how cells restart DNA replication downstream of a genetic lesion.

What was unique about your approach to the research?
We approached the mechanisms of the replication stress response from a new perspective. DNA replication is a bi-directional process that results in one continuous and one discontinuous newly synthesized strand called the leading and lagging strands, respectively. Most studies investigate genotoxic agents that affect both strands of DNA, but this study used an alternative methodology that preferentially stalled the lagging strand, allowing us to study the impact of these agents on a single strand.

What were your findings?
PRIMPOL is a protein that restarts DNA synthesis after damage stalls replication, which results in a gap in the DNA because synthesis is restarted after skipping the DNA lesion. Our work found that the checkpoint protein CHK1—a therapeutic target that allows cancer cells to become resistant to chemotherapeutics—regulates the activity of PRIMPOL. By understanding the regulation of PRIMPOL by CHK1, we may gain insight into certain types of cancers that are associated with gaps in the DNA strand, including how cancers become resistant to therapeutic regimens.

What do you hope will be achieved with the research results in the short and long terms?
In the short term, this research uncovers a mechanism by which PRIMPOL can be quickly regulated—by regulating CHK1 activity—which will be important for the field to understand the replication stress repose in greater detail. The work provides a foundation for us and others in the field to investigate strand-specific DNA repair mechanisms. In the long term, we hope this work provides some insight into future therapeutic regimens for cancer treatments.

Where is this research taking you next?
There is still much to be learned about the mechanisms regulating DNA repair. Future work could investigate other factors that are involved in regulating the replication stress response. We are also interested in understanding how CHK1 induces the activity of PRIMPOL.

This work was funded by the National Institutes of Health and the Breast Cancer Research Foundation.