Enzyme associated with premature aging also has key role in replication of certain cancer cells

January 20, 2022

Aging Biology Genetics Translational Research

Understanding how WRN helicase, a DNA-unwinding enzyme, functions may help researchers learn how to target treatment-resistant BReast CAncer gene 2 (BRCA2)-mutated cancer cells. In a study supported in part by NIA, inhibiting WRN helicase in female mice led to increased death of BRCA2-mutated cancer cells and boosted the ability of an anticancer drug to stop them from replicating. Findings from the study were recently published in Nature Communications.

The WRN helicase enzyme is genetically linked with Werner syndrome, a premature aging disorder associated with increased risk of cancer. Additionally, mutations — or DNA sequence changes — in the BRCA2 gene disrupt the process of DNA replication and increase the risk of breast and ovarian cancer. Anticancer drugs, such as cytotoxic chemotherapies, attempt to stop their replication and kill the cancer cells. However, many cancer cells can continue to undergo DNA replication and proliferate, or multiply, despite DNA damage.

Graph showing how mutated cells replicate, both with and without the change in the DNA — Credit: Robert M. Brosh Jr., PhD., senior investigator, Translational Gerontology Branch, NIA

NIH scientists from NIA and NCI, in collaboration with colleagues at the Pennsylvania State University College of Medicine, used an investigative procedure called single-molecule DNA fiber assay to visualize DNA replication in living BRCA2-mutated cancer cells. The researchers were able to determine how WRN helicase remodels the stalled, or paused, DNA replication process in cancer cells in order to reactivate the process.

In a unique translational research approach, the research team put human BRCA2-mutated cancer cells in female mice without immune systems and pharmacologically targeted WRN helicase to stop remodeling activity. The suppression of WRN function increased cancer cell damage and inhibited BRCA2-mutated tumor growth in the mouse model. Furthermore, treatment of human BRCA2-mutated cancer cells with the WRN-inhibiting compound increased the cytotoxicity of a DNA repair inhibitor drug currently being used to treat cancer patients whose tumors can become resistant. This suggests a promising avenue to cut off an important backup strategy of cancer cells that enables them to survive and proliferate even in the face of cytotoxic chemotherapy.

Better understanding of cancer cell strategies may offer new opportunities for improving the effectiveness of anticancer drugs and treatments. Future study of DNA replication stabilization mechanisms in cancer cells could continue to identify and target specific genetic backdoors. There may also be research applications for WRN helicase inhibition as it relates to premature aging.

This research was supported in part by NIA grant 1ZIAAG000741-19.

Reference: Datta A, et al. WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells. Nature Communications. 2021;12(1):6561. doi: 10.1038/s41467-021-26811-w.