New pathway for stalling BRCA tumor growth revealed

Feb. 2, 2015

Inhibiting the action of a particular enzyme dramatically slows the growth of tumor cells tied to BRCA1 and BRCA2 genetic mutations which, in turn, are closely tied to breast and ovarian cancers, according to researchers at NYU Langone Medical Center.

Senior investigator and NYU Langone cell biologist Agnel Sfeir, PhD, says 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 findings were recently published in the journal Nature.

Researchers say their discovery about the enzyme — called polymerase theta, or PolQ — resulted from efforts to answer a fundamental biological 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 telomeres broken as part of cell metabolism. But such fusions, the researchers say, compromise normal cell growth and survival.

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 tumors, including breast and ovarian, but also in liver and colon cancers. Breast and ovarian cancers are among the leading causes of cancer death among women in the United States.

Additional experiments confirmed that PolQ is needed to activate the alt-NHEJ pathway of DNA repair. Unlike the main, error-free pathway — or HDR 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.

Read the article preview on the Nature website