DNA repair by MGMT, but not AAG, causes a threshold in alkylation-induced colorectal carcinogenesis.

Abstract

Epidemiological studies indicate that N-nitroso compounds (NOC) are causally linked to colorectal cancer (CRC). NOC induce DNA alkylations, including O (6)-methylguanine (O (6)-MeG) and N-methylated purines, which are repaired by O (6)-MeG-DNA methyltransferase (MGMT) and N-alkyladenine-DNA glycosylase (AAG)-initiated base excision repair, respectively. In view of recent evidence of nonlinear mutagenicity for NOC-like compounds, the question arises as to the existence of threshold doses in CRC formation. Here, we set out to determine the impact of DNA repair on the dose-response of alkylation-induced CRC. DNA repair proficient (WT) and deficient (Mgmt (-/-), Aag (-/-) and Mgmt (-/-)/Aag (-/-)) mice were treated with azoxymethane (AOM) and dextran sodium sulfate to trigger CRC. Tumors were quantified by non-invasive mini-endoscopy. A non-linear increase in CRC formation was observed in WT and Aag (-/-) mice. In contrast, a linear dose-dependent increase in tumor frequency was found in Mgmt (-/-) and Mgmt (-/-)/Aag (-/-) mice. The data were corroborated by hockey stick modeling, yielding similar carcinogenic thresholds for WT and Aag (-/-) and no threshold for MGMT lacking mice. O (6)-MeG levels and depletion of MGMT correlated well with the observed dose-response in CRC formation. AOM induced dose-dependently DNA double-strand breaks in colon crypts including Lgr5-positive colon stem cells, which coincided with ATR-Chk1-p53 signaling. Intriguingly, Mgmt (-/-) mice displayed significantly enhanced levels of γ-H2AX, suggesting the usefulness of γ-H2AX as an early genotoxicity marker in the colorectum. This study demonstrates for the first time a non-linear dose-response for alkylation-induced colorectal carcinogenesis and reveals DNA repair by MGMT, but not AAG, as a key node in determining a carcinogenic threshold.

• Authors: Jörg Fahrer, Janina Frisch, Georg Nagel, Alexander Kraus, Bastian Dörsam, Adam D Thomas, Sonja Reißig, Ari Waisman, Bernd Kaina
• Journal: Carcinogenesis (Carcinogenesis) Vol. 36 Issue 10 Pg. 1235-44 (Oct 2015) ISSN: 1460-2180 [Electronic] England
• PMID: 26243310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Nitroso Compounds
• Tumor Suppressor Proteins
• DNA Modification Methylases
• MGMT protein, mouse
• 3-methyladenine-DNA glycosylase
• DNA Glycosylases
• DNA Repair Enzymes

Topics

• Animals
• Carcinogenesis (chemically induced, genetics)
• Colorectal Neoplasms (chemically induced, genetics, pathology)
• DNA Glycosylases (genetics)
• DNA Modification Methylases (genetics)
• DNA Repair (drug effects, genetics)
• DNA Repair Enzymes (genetics)
• Disease Models, Animal
• Humans
• Mice
• Mice, Transgenic
• Nitroso Compounds (toxicity)
• Tumor Suppressor Proteins (genetics)