Navigation Links
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.

'"/>




Related medicine news :

1. Little sleep as bad as no sleep
2. Aspirin Induced Asthma , A Little-Known Inducer
3. A Little Weight Loss Found To Make A Significant Difference In Men
4. Little Clinic LLC Plans Super Medical Clinics in Publix Super Markets
5. Trendsetters: Little girls fast track into ladies even before they know it
6. The Little Known Facts of Junk DNA
7. Too Much Or Little Sleep Increases Risk Of Diabetes
8. Diabetes Risk Pronounced With Too Much or Too Little Sleep
9. Reverse Heart Transplant Surgery On A Little Girl Makes History
10. Most People With Arthritis Do Little Or No Exercise At All
11. Little Makoda-Poster Girl For Leukemia Awareness Campaign Losses Her Battle Of Life
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:4/25/2017)... ... April 25, 2017 , ... Splashtop ... Mirroring360 Pro . This new addition to the Mirroring360 product family combines device ... business. , Mirroring360 Pro enables educators, business professionals and individuals to stream or ...
(Date:4/25/2017)... ... April 25, 2017 , ... As President ... are preparing for how his administration could impact the employee benefits industry. James ... changes are most likely to make it through Congress. His discussion will focus ...
(Date:4/25/2017)... ... April 25, 2017 , ... Patients who would like to ... a fraction of the time as traditional braces – Wilckodontics®. Dr. Victoria Chen, ... offers this revolutionary treatment with or without a referral. , Wilckodontics is ...
(Date:4/25/2017)... ... 2017 , ... Buyers and sellers in the thriving multi-billion dollar cannabis marketplace ... help but be heartened by the industry’s current surge. But another thing that unifies ... smell.” At last they can simply, safely and effectively end their aroma anguish ...
(Date:4/25/2017)... Fl (PRWEB) , ... April 25, 2017 , ... There ... Memorial Regional Hospital, according to a special report in the May issue of Consumer ... its highest quality ranking for results achieved during and after coronary bypass and ...
Breaking Medicine News(10 mins):
(Date:4/19/2017)... , April 19, 2017 ... an immune response in pets such as canine, ... are of various types such as Attenuated Live ... Vaccines, DNA Vaccines and Recombinant Vaccines. Attenuated live ... virus or bacteria, which have been weakend under ...
(Date:4/18/2017)...  Cardinal Health (NYSE: CAH ) today ... per share (EPS) guidance and providing a preliminary view ... with this morning,s announcement of the planned acquisition of ... businesses. Cardinal Health now believes that fiscal ... the bottom of its previous guidance range of $5.35 ...
(Date:4/18/2017)... 18, 2017  Astute Medical, Inc., developer of biomarkers ... be presented at the 2017 National Kidney Foundation (NKF) ... continues through April 22. Physicians will present data on ... assess risk for acute kidney injury (AKI) during the ... Elevated levels of TIMP-2 and IGFBP-7 ...
Breaking Medicine Technology: