Faculty & Staff Directory

Research:

The broad aim of the Cheng laboratory is to determine the molecular events that lead to aging. Our research interests include the investigation of 1) molecular mechanisms of the DNA damage response associated with aging and cancer; 2) selenium regulation on genomic stability.

In the past decade, it has become apparent that the rate of aging can be regulated by a number of critical proteins that play important roles in genomic maintenance. Werner syndrome and Ataxia-telengiectasia are human genetic disorders characterized by clinical features of premature aging and cancer predisposition. WRN and ATM are proteins shown to be involved in DNA metabolic events, including DNA replication, DNA damage repair and cell checkpoint regulation. In addition, dietary factors have been demonstrated to influence the processes of DNA metabolism and aging. Selenium, an essential nutrient, exerts its biological functions mainly through a class of selenocysteine-containing proteins called selenoproteins. Interestingly, selenium is currently the only agent with demonstrated cancer prevention effect.

Our laboratory is currently investigating the causes of aging-associated diseases as well as tumorigenesis. By employing cellular and mouse models for genomic instability, we are presented with a unique opportunity to examine the molecular effect of selenium on aging and cancer. We propose that the maintenance of genomic integrity can be modulated by dietary antioxidants such as selenium. Therefore, one of our goals is to understand nutritional impact on DNA damage response and aging at the molecular level.

We employ a broad range of biological approaches to address specific hypotheses. Research approaches include basic molecular genetics, biochemistry, cytogenetics, genomics and mouse-based models.

Selected Publications:

Original Research

• Agrelo R, Cheng W-H, Setien F, Espada J, Fraga MF, Herranz M, Paz MF, Sanchez-Cespedes M, Artiga MJ, Guerrero D, Castells A, von Kobbe C, Bohr VA, Esteller M. 2006. Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proc. Natl. Acad. Sci. 103: 8822-8827.
• Cheng W-H, Kusumoto R, Opresko PL, Sui X, Huang S, Nicolette ML, Paull TT, Campisi J, Seidman M, Bohr VA. 2006. Collaboration of Werner syndrome protein and BRCA1 in cellular responses to DNA interstrand cross-links, Nucleic Acids Research. 34: 2751-2760.
• Cheng W-H, Sakamoto S, Fox JT, Komatsu K, Carney J, Bohr VA. 2005. Werner syndrome protein associates with gamma-H2AX in a manner that depends upon Nbs1. FEBS Letters 579:1350-1356.
• Cheng W-H, von Kobbe C, Opresko PL, Arthur LM, Seidman MM, Carney JP, Komatsu K, Bohr VA. 2004. Linkage between Werner syndrome protein and the Mre11 complex via Nbs1. J. Biol. Chem. 279:1169-1176.
• Cheng W-H, von Kobbe C, Opresko PL, Ren J, Kufe D, Bohr VA. 2003. Werner syndrome protein phosphorylation by Abl tyrosine kinase regulates its activity and distribution. Mol. Cell. Biol. 23: 6385-6395.
• Kyng KJ, May A, Brosh, Jr. RM, Cheng W-H, Chen C, Becker KG, Bohr VA. 2003. The transcriptional response after oxidative stress is defective in Cockayne syndrome group B cells. Oncogene 22: 1135-1149.
• Cheng W-H, Quimby FR, Lei XG. 2003. Impacts of glutathione peroxidase-1 knockout on the protection by injected selenium against the pro-oxidant-induced liver aponecrosis and signaling in selenium-deficient mice. Free Radical Biology & Medicine 34:918-927.
• Cheng W-H, Zheng X, Quimby FR, Roneker CA, Lei XG. 2003. Low levels of glutathione peroxidase 1 activity in selenium-deficient mouse liver affect c-Jun N-terminal kinase activation and p53 phosphorylation on Ser-15 in pro-oxidant-induced aponecrosis. Biochem. J. 370:927-934.
• Cheng W-H, Fu Y, Porres JM, Ross DA, Lei XG. 1999. Selenium-dependent cellular glutathione peroxidase protects mice against a pro-oxidant-induced oxidation of NADPH, NADH, lipids, and protein. FASEB J. 13: 1467-1475.
• Cheng W-H, Valentine BA, Lei XG. 1999. High levels of dietary vitamin E do not replace cellular glutathione peroxidase in protecting mice from acute oxidative stress. J. Nutr. 129: 1951-1957.
• Porres JM, Stahl CH, Cheng W-H, FuY , Roneker KR, Pond WG, Lei XG. 1999. Dietary intrinsic phytate protects colon from lipid peroxidation in pigs with a moderately high dietary iron intake. Proceedings of the Society for Experimental Biology and Medicine 221: 80-86.
• Cheng W-H, Combs, Jr. GF, Lei XG. 1998. Knockout of cellular glutathione peroxidase affects selenium-dependent parameters similarly in mice fed adequate and excessive dietary selenium. Biofactors 7: 311-321.
• Cheng W-H, Ho Y-S, Valentine BA, Ross DA, Combs, Jr. GF, Lei XG. 1998. Cellular glutathione peroxidase is the mediator of body selenium to protect against paraquat lethality in transgenic mice. J. Nutr. 128: 1070-1076.
• Cheng W-H, Ho Y-S, Ross DA, Valentine BA, Combs, Jr. GF, Lei XG. 1997. Cellular glutathione peroxidase knockout mice express normal levels of selenium-dependent plasma and phospholipid hydroperoxide glutathione peroxidase in various tissues. J. Nutr. 12: 1445-1450.
• Cheng W-H, Ho Y-S, Ross DA, Han Y, Combs, Jr. GF, LeiXG. 1997. Overexpression of cellular glutathione peroxidase does not affect expression of plasma glutathione peroxidase or phospholipid hydroperoxide glutathione peroxidase in mice offered diets adequate or deficient in selenium. J. Nutr. 127:475-480.

Refereed Reviews

• Cheng W-H, Muftuoglu M, Bohr VA. 2007 (in press). Werner syndrome protein: functions in the response to DNA damage and replication stress in S-phase. Experimental Gerontology.
• Lei XG, Cheng W-H, McClung J. 2007. Metabolic regulation and function of glutathione peroxidase-1. Annu. Rev. Nutr. 27:41-61.
• Lei XG, Cheng W-H. 2005. New Roles for an Old Selenoenzyme: Evidence from Glutathione Peroxidase-1 Null and Overexpressing Mice. J. Nutr. 135:2295-2298.
• Opresko PL, Cheng W-H, Bohr VA. 2004. At the junction of RecQ helicase biochemistry and human disease. J. Biol. Chem. 27:18099-18102.