Study Identifies New Pathway for Stalling BRCA-Mutated Tumor Growth in Mice and Human Cells
Inhibiting the action of a particular enzyme dramatically slows the growth of tumor cells tied to BRCA1 and BRCA2 genetic mutations that are closely tied to breast and ovarian cancers, according to researchers at New York University (NYU) Langone Medical Center.
Senior investigator Agnel Sfeir, PhD, said that if further experiments prove successful, these findings could lead to a new class of targeted therapies against cancers with BRCA1 and BRCA2 mutations. The researchers’ findings in experiments in mice and human cells are described by Mateos-Gomez et al in the journal Nature.
Polymerase Theta
Researchers say their discovery about the enzyme—called polymerase theta, or PolQ—resulted from efforts to answer a fundamental biologic question: How do cells prevent the telomere ends of linear chromosomes, which house our genetic material, from sticking together? Cell DNA repair mechanisms can stitch together broken telomeres as part of cell metabolism. But such fusions, the researchers say, compromise normal cell growth and survival.
“In the purest biological sense, our findings show how PolQ, which we know is active in several tumors, promotes unwanted telomere fusions by inserting whole segments of DNA via a disruptive DNA repair pathway termed alt-NHEJ,” said Dr. Sfeir, Assistant Professor of Cell Biology at NYU Langone and Skirball Institute for Biomolecular Medicine. “It was quite remarkable to find that by blocking PolQ action, cancer cell growth was cut by more than half.”
Study Details
For the study, Dr. Sfeir and colleagues at the Scripps Research Institute focused their analysis on telomeric DNA. They noted that as the chromosome ends were being joined, whole sections of new genetic material were being inserted into the telomeric DNA — suggesting that any of a dozen or more DNA-synthesizing polymerase enzymes were at work. Researchers then focused on PolQ, in part because it is known to be active in several cancers, primarily breast and ovarian, but also liver and colon.
Additional experiments confirmed that PolQ is needed to activate the alt-NHEJ pathway of DNA repair. Unlike the main, error-free pathway, the alt-NHEJ pathway does not use a related chromosome’s genetic material as a template to meticulously correct any damaged genetic material. As such, alt-NHEJ is highly likely to leave coding mistakes.
“Our studies will continue to look at how the alt-NHEJ pathway operates,” Dr. Sfeir added, “and what biological factors cells use in addition to PolQ to choose between the error-prone or error-free DNA repair pathways.”
Dr. Sfeir is the corresponding author for the Nature article.
The study was supported by the Breast Cancer Alliance, the V-Foundation, the U.S. Department of Defense Breast Cancer Research Program, the Pew-Stewart Scholars Program for Cancer Research, the Novartis Advanced Discovery Institute, the National Institutes of Health, the Helen L. and Martin S. Kimmel Center for Stem Cell Biology, the University of Texas at Austin, and from the Cancer Prevention Research Institute of Texas.
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