New Enzyme Pathway May Inhibit BRAC1 and BRAC2 Tumor Growth

Agnel Sfeir PhD Assistant Professor  Skirball Institute - NYU  New York, NY Interview with:
Agnel Sfeir PhD Assistant Professor 

Skirball Institute – NYU
New York, NY 10016

Medical Research: What is the background for this study? What are the main findings?

Dr. Sfeir: The main finding of this study, published in the journal Nature, is that 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.

This 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.

In the purest biological sense, our findings (in experiments in mice and human cells) show how this particular enzyme, 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. It was quite remarkable to find that by blocking PolQ action, cancer cell growth was cut by more than half.

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.

Medical Research: What should clinicians and patients take away from your report?

Dr. Sfeir: If further experiments prove successful, these findings could lead to a new class of targeted therapies against cancers with BRCA1 and BRCA2 mutations.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Sfeir: Our studies will continue to look at how the alt-NHEJ pathway operates,” Dr. Sfeir adds, “and what biological factors cells use in addition to PolQ to choose between the error-prone or error-free DNA repair pathways.


Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination

Pedro A. Mateos-Gomez, Fade Gong, Nidhi Nair, Kyle M. Miller, Eros Lazzerini-Denchi & Agnel Sfeir
Nature doi:10.1038/nature14157

[wysija_form id=”1″] Interview with:  Agnel Sfeir PhD Assistant Professor (2015). New Enzyme Pathway May Inhibit BRAC1 and BRAC2 Tumor Growth