Aberrant repair of etheno-DNA adducts in leukocytes and colon tissue of colon cancer patients.

Abstract

To assess the role of lipid peroxidation-induced DNA damage and repair in colon carcinogenesis, the excision rates and levels of 1,N(6)-etheno-2'-deoxyadenosine (epsilondA), 3,N(4)-etheno-2'-deoxycytidine (epsilondC), and 1,N(2)-etheno-2'-deoxyguanosine (1,N(2)-epsilondG) were analyzed in polymorphic blood leukocytes (PBL) and resected colon tissues of 54 colorectal carcinoma (CRC) patients and PBL of 56 healthy individuals. In PBL the excision rates of 1,N(6)-ethenoadenine (epsilonAde) and 3,N(4)-ethenocytosine (epsilonCyt), measured by the nicking of oligodeoxynucleotide duplexes with single lesions, and unexpectedly also the levels of epsilondA and 1,N(2)-epsilondG, measured by LC/MS/MS, were lower in CRC patients than in controls. In contrast the mRNA levels of repair enzymes, alkylpurine- and thymine-DNA glycosylases and abasic site endonuclease (APE1), were higher in PBL of CRC patients than in those of controls, as measured by QPCR. In the target colon tissues epsilonAde and epsilonCyt excision rates were higher, whereas the epsilondA and epsilondC levels in DNA, measured by (32)P-postlabeling, were lower in tumor than in adjacent colon tissue, although a higher mRNA level was observed only for APE1. This suggests that during the onset of carcinogenesis, etheno adduct repair in the colon seems to be under a complex transcriptional and posttranscriptional control, whereby deregulation may act as a driving force for malignancy.

• Authors: Tomasz Obtułowicz, Alicja Winczura, Elzbieta Speina, Maja Swoboda, Justyna Janik, Beata Janowska, Jarosław M Cieśla, Paweł Kowalczyk, Arkadiusz Jawien, Daniel Gackowski, Zbigniew Banaszkiewicz, Ireneusz Krasnodebski, Andrzej Chaber, Ryszard Olinski, Jagadesaan Nair, Helmut Bartsch, Thierry Douki, Jean Cadet, Barbara Tudek
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 49 Issue 6 Pg. 1064-71 (Sep 15 2010) ISSN: 1873-4596 [Electronic] United States
• PMID: 20600828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• 1,N(6)-etheno-2'-deoxyadenosine
• DNA Adducts
• Deoxyadenosines
• Deoxycytidine
• 3,N(4)-ethenodeoxycytidine
• DNA Glycosylases
• Thymine DNA Glycosylase
• DNA-3-methyladenine glycosidase II
• APEX1 protein, human
• DNA-(Apurinic or Apyrimidinic Site) Lyase

Topics

• Adult
• Aged
• Carcinoma (genetics, metabolism, pathology, physiopathology)
• Case-Control Studies
• Colon (metabolism, pathology)
• Colonic Neoplasms (genetics, metabolism, pathology, physiopathology)
• DNA Adducts (metabolism)
• DNA Glycosylases (genetics, metabolism)
• DNA Repair (genetics)
• DNA-(Apurinic or Apyrimidinic Site) Lyase (genetics, metabolism)
• Deoxyadenosines (metabolism)
• Deoxycytidine (analogs & derivatives, metabolism)
• Female
• Humans
• Leukocytes, Mononuclear (metabolism, pathology)
• Lipid Peroxidation
• Middle Aged
• Mutation (genetics)
• Thymine DNA Glycosylase (genetics, metabolism)