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Little Known DNA Repair Enzyme May Be A Tumor Suppressor Gene

Researchers at the University of Pittsburgh have demonstrated that loss of DNA // repair enzyme’s activity in mouse cells leads to dramatic chromosomal instability.

The DNA in our cells is constantly subject to environmental, chemical and cellular impacts. Thanks to nature, our cells contain several enzymes dedicated to detecting and repairing any damage caused by these impacts. Failure of these enzymes to make needed repairs to genes in time can lead to the accumulation of mutations and, eventually, cell death or probably cancer. The activity of some DNA repair enzymes appears to be more crucial than others, particularly in developing embryos.

University of Pittsburgh researchers report in the January 1 edition of Cancer Research that a poorly understood enzyme, DNA polymerase zeta, also known as pol zeta, has the uncanny ability to give even heavily damaged DNA a new lease of life. When this enzyme is absent in cells that has already growth control problems, the consequences to chromosomes are catastrophic and may lead to cancer.

"Pol zeta appears to be the only one of a group of specialized DNA polymerases that is critical for development in animals," says John P. Wittschieben, Ph.D., research instructor in the department of pharmacology, University of Pittsburgh School of Medicine, and first author of the study. "Its loss in animal cells drastically affects the development of chromosomal stability, which is a hallmark of cancer. Therefore, we believe its function may be to suppress the development of tumors."

Although DNA polymerases—enzymes responsible for copying, editing and repairing genes and surrounding DNA—generally have the ability to make accurate copies of strands of DNA, damaged areas, called lesions, can bring this replication machinery to a complete halt in certain areas. In the last few years, scientists have learned of the existence of several so-called lesion-replicating polymerases that can overcome th ese replication "stop signs" and keep cells dividing that would otherwise be killed off by their own suicide mechanisms.

First discovered in budding yeast cells, and later in plants and animals, pol zeta has the remarkable ability to efficiently extend, in the test tube, DNA with lesions that stop most other DNA polymerases in their tracks. Research has shown that inactivation of this lesion-replicating enzyme in yeast leads to a dramatic decrease in the frequency of mutations induced by a wide range of DNA damaging agents.

In this study, Dr. Wittschieben and his associates sought to determine pol zeta's key role in mice cells. To do this, they disabled or "knocked out" the gene for pol zeta's Rev3L subunit, the part with the lesion-replicating capabilities. However, knocking out the Rev3L gene proved lethal to the mice embryos. All the same, fibroblasts were isolated from these embryos to see if they could be kept alive in culture. After repeated attempts, the mouse embryonic fibroblasts, or MEFs, failed to divide and died within a few weeks or months.

Suspecting that the MEFs died because they were self-destructing, or undergoing apoptosis, the investigators then knocked out the gene for a protein known as p53, which is a cell-suicide-signaling molecule. After matings between the p53 knockout mice and Rev3L knockout mice, the investigators isolated and cultured MEFs from all the offspring of the matings to see if any would grow. To start with, the cells all failed to divide. However, three months later, some cells began to grow and at a surprisingly robust rate.

Dr. Wittschieben said, "Since the only Rev3L-deficient cells that began dividing also were p53 deficient, we believe that knocking out their apoptotic mechanism was key to this viability. However, they didn't begin dividing right away, so something else must have happened. We are still not sure what it is."

When the investigators wondered why these cell s were different from normal cells, they found that the cells' chromosomes showed not only a dramatic ten-fold increase in the incidence of swapping and fusing of genes and other genetic material between chromosomes, but also an increase in the number of chromosomes compared to normal cells.

The high frequency of DNA rearrangements in Rev3L/p53-deficient cells suggests that pol zeta in normal cells is responsible for preventing double-stranded breaks in chromosomes. When pol zeta is absent, it leads to a massive amount of double-stranded breaks, some of which are repaired correctly and others that are repaired incorrectly by being fused to other genes or chromosomes.

These findings have significant implications for human cancer research, as such a high degree of chromosomal instability is a characteristic of cancer cells. Further, the human Rev3L gene is located in a segment of chromosome 6 which is home for multiple tumor suppressor genes and a slew of human cancers, including a number of leukemias and lymphomas. This segment is associated with chromosomal instabilities in this particular region of chromosome 6.

"Although it requires further investigation, we believe that mutations in this part of chromosome 6 could occur during the development of some cancers and this may have prognostic and therapeutic implications. We are now investigating this hypothesis by selectively deleting the Rev3L gene in adult mouse cells to study how the loss of DNA polymerase zeta influences the development and progression of spontaneous cancers," the researchers explained.

This work was supported by a grant from the National Cancer Institute, National Institutes of Health to Dr. Wood. In addition to Drs. Wittschieben and Wood, others involved in this study include Shalini C. Reshmi, Ph.D., and Susan M. Gollin, Ph.D., University of Pittsburgh Graduate School of Public Health.

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