| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Carcinogenesis |
Department of Cellular and Molecular Physiology, The Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033
O6-Alkylguanine-DNA alkyltransferase (AGT) plays a critical role in protection from the carcinogenic effects of simple alkylating agents by repairing O6-alkylguanine adducts via a direct transfer reaction. Nitric oxide (NO) or species derived from it are known to be able to initiate neoplastic growth and cannot only damage DNA, either directly or via the formation of intermediates such as nitrosamines, but can also inhibit some DNA repair processes. We have studied the inactivation of AGT by NO in detail in vitro and in vivo using wild-type human AGT (hAGT) and mutants at key residues. Our results show that hAGT is readily but reversibly inactivated by the formation of S-nitrosylcysteine at Cys-145, which is the alkyl acceptor site. The facile reaction of this cysteine residue with NO is attributable to its interaction with other residues in hAGT including His-146 and Glu-172 that activate the sulfhydryl group of Cys-145 to allow its nucleophilic attack on DNA adducts. Although the S-nitrosylcysteine adduct in hAGT is readily reversible by reaction with other cellular thiols, the formation of S-nitrosocysteine at Cys-145 was found to lead to the rapid degradation of the hAGT protein in vivo. This degradation is brought about by the ubiquitin/proteasomal system. The formation of an S-nitrosylcysteine at Cys-145 in hAGT in response to NO led to a large increase in the ubiquitination of the protein. This NO-mediated increase did not occur with the C145S or C145A mutants. A conformational change in hAGT, which involves opening of an asparagine hinge, normally occurs after alkylation of the protein in its role in DNA repair and causes degradation of the alkylated hAGT. Our results indicate that a similar effect occurs after reaction of the protein with NO. Thus, exposure to NO causes an irreversible loss of DNA repair capacity for alkylation adducts. This may contribute toward the potential development of tumors in cells upon chronic exposure to NO because of inflammation or infection. This may be of particular importance because such exposure may also lead to the formation of N-nitroso compounds that can act as alkylating agents.
This article has been cited by other articles:
|
|
 |
|
  R. Guza, L. Ma, Q. Fang, A. E. Pegg, and N. Tretyakova Cytosine Methylation Effects on the Repair of O6-Methylguanines within CG Dinucleotides J. Biol. Chem., August 21, 2009; 284(34): 22601 - 22610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Remington, J. Chtchetinin, K. Ancheta, P. L. Nghiemphu, T. Cloughesy, and A. Lai The L84F polymorphic variant of human O6-methylguanine-DNA methyltransferase alters stability in U87MG glioma cells but not temozolomide sensitivity Neuro-oncol, January 1, 2009; 11(1): 22 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Pang, X. Zhou, H. Yu, M. Dong, K. Taghizadeh, J. S. Wishnok, S. R. Tannenbaum, and P. C. Dedon Lipid peroxidation dominates the chemistry of DNA adduct formation in a mouse model of inflammation Carcinogenesis, August 1, 2007; 28(8): 1807 - 1813. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Mijal, S. Kanugula, C. C. Vu, Q. Fang, A. E. Pegg, and L. A. Peterson DNA Sequence Context Affects Repair of the Tobacco-Specific Adduct O6-[4-Oxo-4-(3-pyridyl)butyl]guanine by Human O6-Alkylguanine-DNA Alkyltransferases. Cancer Res., May 1, 2006; 66(9): 4968 - 4974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wu, K. Takenaka, E. Sonoda, H. Hochegger, S. Kawanishi, T. Kawamoto, S. Takeda, and M. Yamazoe Critical Roles for Polymerase {zeta} in Cellular Tolerance to Nitric Oxide-Induced DNA Damage Cancer Res., January 15, 2006; 66(2): 748 - 754. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Suzuki, K Iijima, G Scobie, V Fyfe, and K E L McColl Nitrate and nitrosative chemistry within Barrett's oesophagus during acid reflux Gut, November 1, 2005; 54(11): 1527 - 1535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Ritchey, W.-Y. Huang, A. P. Chokkalingam, Y.-T. Gao, J. Deng, P. Levine, F. Z. Stanczyk, and A. W. Hsing Genetic Variants of DNA Repair Genes and Prostate Cancer: A Population-Based Study Cancer Epidemiol. Biomarkers Prev., July 1, 2005; 14(7): 1703 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kanugula, G. T. Pauly, R. C. Moschel, and A. E. Pegg A bifunctional DNA repair protein from Ferroplasma acidarmanus exhibits O6-alkylguanine-DNA alkyltransferase and endonuclease V activities PNAS, March 8, 2005; 102(10): 3617 - 3622. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K E L McColl When saliva meets acid: chemical warfare at the oesophagogastric junction Gut, January 1, 2005; 54(1): 1 - 3. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M H Derakhshan, A Yazdanbod, A R Sadjadi, B Shokoohi, K E L McColl, and R Malekzadeh High incidence of adenocarcinoma arising from the right side of the gastric cardia in NW Iran Gut, September 1, 2004; 53(9): 1262 - 1266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. T. Donnelly, H. Bardwell, G. A. Thomas, E. D. Williams, M. Hoper, P. Crowe, W. G. McCluggage, M. Stevenson, D. H. Phillips, A. Hewer, et al. Modulation of N-methyl-N-nitrosourea-induced crypt restricted metallothionein immunopositivity in mouse colon by a non-genotoxic diet-related chemical Carcinogenesis, May 1, 2004; 25(5): 847 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Liu, D. L. Hachey, G. Valadez, K. M. Williams, F. P. Guengerich, N. A. Loktionova, S. Kanugula, and A. E. Pegg Characterization of a Mutagenic DNA Adduct Formed from 1,2-Dibromoethane by O6-Alkylguanine-DNA Alkyltransferase J. Biol. Chem., February 6, 2004; 279(6): 4250 - 4259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Iijima, J. Grant, K. McElroy, V. Fyfe, T. Preston, and K. E. L. McColl Novel mechanism of nitrosative stress from dietary nitrate with relevance to gastro-oesophageal junction cancers Carcinogenesis, December 1, 2003; 24(12): 1951 - 1960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Liu, A. E. Pegg, K. M. Williams, and F. P. Guengerich Paradoxical Enhancement of the Toxicity of 1,2-Dibromoethane by O6-Alkylguanine-DNA Alkyltransferase J. Biol. Chem., September 27, 2002; 277(40): 37920 - 37928. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
