Carol Bernstein
Research Associate Professor of Cell Biology and Anatomy
Mail:
Arizona Health Sciences Center Room 6108
Cell Biology and Anatomy Department
P.O. Box 245044
Tucson AZ 85724-5044
Phone: 520/626-6069
Fax: 520/626-2097
e-mail: bernstein3@earthlink.net
Summary of Research Activities in two areas:
*Aging, Sex and DNA Repair
*Etiology of Cancer of the Gastrointestinal Tract
Relationship of DNA repair to sex and aging
Aging appears to be a consequence of DNA damage, while sexual reproduction (sex) appears to be an adaptation for coping with both DNA damage and mutation. DNA, the genetic material of most organisms, is composed of molecular subunits which are not endowed with any peculiar chemical stability. Thus DNA is subject to a wide variety of chemical reactions that might be expected of any such molecule in a warm aqueous medium. DNA damages are known to occur very frequently and organisms have evolved enzymemediated repair processes to cope with them. In any cell, however, some DNA damage may remain unrepaired despite repair processes. Aging seems to be due to the accumulation of unrepaired DNA damage in somatic cells, especially in non-dividing cells such as those in mammalian brain and muscle.
On the other hand, the primary function of sex appears to be the repair of damages in germ cell DNA, through efficient recombinational repair when chromosomes pair during the sexual process. This allows an undamaged genome to initiate the next generation. In addition, in diploid organisms, sex allows chromosomes from genetically unrelated individuals (parents) to come together in a common cytoplasm (that of progeny). Since genetically unrelated parents ordinarily would not have common mutations, the chromosomes present in the progeny should complement each other, masking expression of any deleterious mutations that might be present.
Thus, aging and sex appear to be two sides of the same coin. Aging reflects the accumulation of DNA damage and sex reflects the removal of DNA damage plus, in diploid organisms, the masking of mutations by complementation.
*Bernstein, Carol and Harris Bernstein. „Aging and Sex, DNA Repair in,‰ in Encyclopedia of Molecular Cell Biology and Molecular Medicine, Vol. 1, Robert A. Meyers, ed., pp. 53-98, Wiley-VCH Verlag GmbH & Co. KGaA Weinheim, Germany 2004.
*Bernstein, Carol, Harris Bernstein, Claire M. Payne and Harinder Garewal. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutation Research Reviews 511:145-178 (2002).
*Bernstein, Carol and Harris Bernstein. DNA Repair in Bacteriophage. In DNA Damage and Repair - Biochemistry, Genetics and Cell Biology, volume 3, pp. 1-19, Jac A. Nickoloff and Merl Hoekstra, eds, Humana Press, Totowa, NJ (2001).
*Bernstein, Carol, Harris Bernstein, Claire Payne. Cell Immortality: Maintenance of Cell Division Potential. pp. 23-50 In: Progress in Molecular and Subcellular Biology Vol.24; Cell Immortalization, Alvaro Macieira-Coelho, ed., Springer Verlag, Heidelberg, Germany, (1999).
BOOK: Bernstein, Carol and Harris Bernstein. Aging, Sex and DNA Repair. Academic Press, pp. 1-382, 1991.
Bile acids, apoptosis and DNA damage; relationship to colon cancer
Bile acids are produced naturally by the body (in the liver) to facilitate emulsification of dietary fats to aid in their digestion. These bile acids are released into the intestinal tract when fats are eaten. Recently, at least 15 different studies have shown that bile acids, at levels comparable to that present after high fat meals, cause DNA damage in mammalian cells. The mechanism appears to involve induction of oxidative stress and production of reactive oxygen species (ROS) by the bile acids. These ROS damage DNA.
Bile acids, like other agents that cause DNA damage, are likely to be carcinogens in the human gastrointestinal tract. Carcinogenicity follows from two effects of DNA damage. First, long-term, repeated DNA damage likely increases the mutation rate, including the mutation rate of tumor suppressor genes and oncogenes. Second, bile acids, at concentrations accompanying a high fat diet, were recently found to induce frequent apoptosis (altruistic cell suicide). In cell populations persistently exposed to bile acids, those cells with reduced capacity to undergo apoptosis tend to survive and selectively proliferate. Cells selected for reduced apoptosis capability would tolerate DNA damage and thus, after replication, tend to have elevated mutation rates. Recently, we showed that patients with a history of colon cancer have reduced apoptosis capability in their colonic mucosal epithelial cells. This indicates a potential for increased colonic mutation and higher risk for carcinogenesis. Thus, the primary cause of colon cancer in modern Western man may be the excessive level of bile acids in the colon due to repeated high-fat meals.
* Bernstein C, Bernstein H, Garewal H, Dinning P, Jabi R, Sampliner RE, McCuskey MK, Panda M, Roe D, L‚Heureux L, Payne CM. A bile acid-induced apoptosis assay for colon cancer risk, and associated quality control studies. Cancer Res 59:2353-2357, 1999.
* Washo-Stultz D, Hoglen N, Bernstein H, Bernstein C, Payne CM. Role of nitric oxide and peroxynitrite in bile salt-induced apoptosis: relevance to colon carcinogenesis. Nutrition and Cancer 35:193-202, 1999.
*Bernstein, Carol, Harris Bernstein, Claire M. Payne and Harinder Garewal. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutation Research Reviews 511:145-178 (2002).
*Bernstein, Harris, Claire M. Payne, Kathleen Kunke, Cara L. Crowley-Weber, Caroline N. Waltmire, Katerina Dvorakova, Hana Holubec, Carol Bernstein, Richard R. Vaillanvourt, Deborah A. Raynes, Vincent Guerriero and Harinder Garewal. A proteomic study of resistance to deoxycholate-induced apoptosis, plus Online Supplemenatry Material at http://www.carcin.oupjournals.org Carcinogenesis 25:681-692 (2004).
*Bernstein, Harris, Carol Bernstein, Claire M. Payne and Harinder Garewal. Bile acids as carcinogens in human gastrointestinal cancers. Reviews in Mutation Research in press 9/06/04
Collaborative Research
* Claire Payne, Ph.D., Cell Biology and Anatomy: Mechanisms of apoptosis
* Harris Bernstein, Ph.D., Cell Biology and Anatomy: Bile acid induced apoptosis
* Harinder Garewal, M.D., Ph.D., Medicine: Gastrointestinal Cancer
* Katerina Dvorakova, Ph.D., Cell Biology and Anatomy: Barretts Esophagus
* Richard Sampliner, M.D., VA Medical Center: Gastrointestinal Cancer
