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DNA Repair Findings Shed Light on Pathways Affecting Cancer Progression

DNA Repair Findings Shed Light on Pathways Affecting Cancer Progression

For healthy cells to become cancerous cells, they have to lose several systems that regulate healthy function such as cell growth and division and DNA repair. New findings from University of Texas at Austin researchers about how one such regulatory system works could aid in efforts to develop personalized treatments for cancer.

Like a watch wrapped around a wrist, a special enzyme encircles the double helix to repair a broken strand of DNA. Without molecules that can mend such breaks, cells can malfunction, die, or become cancerous. Courtesy of Tom Ellenberger, Washington University School of Medicine in St. Louis.

Many forms of cancer have mutations in a gene that produces a protein called ATM, which is involved in regulating DNA repair and cell growth. For some types of cancer, such as lymphomas and leukemias, as many as 50 percent of tumor lines have mutations in this gene.

A team led by Tanya Paull, a molecular biosciences professor who holds the Burl G. and Lorene L. Rogers Chair in Human Health, and post-doctoral fellow Yi Zhou were surprised to find that another regulatory protein, called DNA-PK in turn regulates ATM. It adds yet another puzzle piece to an already large and complicated picture of how our bodies fix so-called double-stranded DNA breaks.

Paull says this kind of understanding is an important step towards personalized medicine, tailoring cancer treatments to a specific tumor's genetic profile.

"Mechanistic understanding of the proteins involved in DNA repair and cell growth is necessary for rational design of treatments based on tumor sequencing data," says Paull, who is also a Howard Hughes Medical Investigator.

The results of this latest study are published on December 8 in the journal Molecular Cell.

They demonstrated the important role of DNA-PK by mutating the gene that produces it and showing that ATM then becomes hyperactive.

Insights by other researchers about the role of other proteins in DNA repair are already yielding promising new treatments for some forms of breast and ovarian cancer. Two human genes, BRCA1 and BRCA2, produce proteins that repair damaged DNA. Certain mutations in either gene prevent cells from repairing their DNA properly and can lead to cancer, but those cancerous cells become even more dependent on other DNA repair pathways. Scientists have found therapies that exploit this vulnerability to attack cancer.

Paull and Zhou's co-authors are Ji-Hoon Lee at UT Austin, and Wenxia Jiang, Jennie L. Crowe and Shan Zha at Columbia University Medical Center.

This research was supported with funding by the Cancer Research and Prevention Institute of Texas and the National Institutes of Health.

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