Research may provide ways to inhibit cancer's ability to resist treatments

03/03/05

Discovery gives clinicians new targets for making existing therapies more effective and developing drugs to inhibit the growth of cancers

A team of researchers at the University of Alberta in Edmonton and the Samuel Lunenfeld Research Institute in Toronto have discovered how a key enzyme involved in repairing DNA is put together and how it works--a development that opens up new therapies for making cancer cells more vulnerable to attack.

The team has crystallized--or characterized in three dimensions--polynucleotide kinase (PNK), a key enzyme involved in a cell's ability to repair single-strand and double-strand breaks in DNA.

"This gives us a clearer picture of how the enzyme works and opens up the possibility that we can develop drugs that inhibit cancer's ability to repair itself and resist treatments," says Biochemistry professor Mark Glover, the lead author in the paper published in today's issue of Molecular Cell.

Normally, explains Department of Oncology and Alberta Cancer Board researcher Michael Weinfeld, when a single- or double-strand break occurs, "the damaged ends need to be cleaned up before they can be rejoined" as an early step in the repair process. PNK is one of the key enzymes required to "polish" the strand break ends. Without it, cells are more sensitive to agents such as ionizing radiation or certain drugs that kill cells by damaging their DNA.

DNA, or deoxyribonucleic acid, is a large molecule shaped like a double helix found primarily in the chromosomes of the cell nucleus and contains the genetic information of the cell. Once damaged, cells have developed biochemical responses to repair the damage; when they can't be repaired, cells die if the damage is too toxic. Or, if the damage is not lethal, mutations can occur that lead to cancer.

The paper is entitled The Molecular Architecture of the Mammalian DNA Repair Enzyme, Polynucleotide Kinase. The work builds on Dr. Weinfeld's work on understanding DNA damage, Dr. Glover's work on the basic biochemical processes involved in understanding breast cancer and Dr. Bernstein's postdoctoral work.

The research was funded by the Canadian Institutes of Health Research, the National Cancer Institute of Canada and the Alberta Heritage Foundation for Medical Research. Dr. Glover is also a Canada Research Chair.

The authors on the paper include: Drs. Glover and Weinfeld, Nina Bernstein, R. Scott Williams, Melissa Rakovszky, Diana Cui, Ruth Green, Feridoun Karimi-Busheri, Rajam Mani, Sarah Galicia, C. Anne Koch, Carol Cass and Daniel Durocher (Dr. Durocher has an appointment with the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto.)

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