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Transgenic systems in studies on genotoxicity of alkylating agents: critical lesions, thresholds and defense
1Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131, Mainz, Germany.
Abstract:
Transgenic systems, both cell lines and mice with gain or loss of function, are being used in order to modulate the expression of DNA repair proteins, thus allowing to assess their contribution to the defense against genotoxic mutagens and carcinogens. In this review, questions have been addressed concerning the use of transgenic systems in elucidating critical primary DNA lesions, their conversion into genotoxic endpoints, low-dose effects, and the relative contribution of individual cellular functions in defense. It has been shown that the repair protein alkyltransferase (MGMT) is decisive for protection against methylating and chloroethylating compounds. Protection pertains also to tumor formation, as revealed by the response of MGMT transgenic and knockout mice. Overexpression of genes involved in base excision repair (N-methylpurine-DNA glycosylase, apurinic endonuclease, DNA polymerase beta) is in most cases not beneficial in increasing the protection level, whereas their down-modulation or inactivation increases cellular sensitivity. This indicates that non-repaired base N-alkylation lesions and/or repair intermediates possess genotoxic potential. Modulation of mismatch repair and poly(ADP)ribosyl transferase has also been shown to affect the cellular response to alkylating agents. Furthermore, the role of Fos, Jun and p53 in cellular defense against alkylating mutagens is discussed.
Insights
Transgenic systems reveal that the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT) is crucial for protection against genotoxic alkylating agents and tumor formation.
Area of Science:
- Molecular Biology
- Genetics
- Toxicology
Background:
- Transgenic systems (cell lines and mice) are vital tools for studying DNA repair mechanisms.
- Understanding DNA repair's role in defending against genotoxic agents is critical for cancer prevention.
Purpose of the Study:
- To review the utility of transgenic systems in assessing DNA repair protein function.
- To elucidate the contribution of specific DNA repair pathways to cellular defense against mutagens.
Main Methods:
- Utilizing transgenic mice and cell lines with altered expression of DNA repair genes.
- Investigating the effects of genotoxic mutagens on these modified systems.
Main Results:
- O6-alkylguanine-DNA alkyltransferase (MGMT) is essential for protection against alkylating agents and prevents tumor formation.
- Overexpressing base excision repair genes offers limited protection; their inactivation increases sensitivity.
- Modulating mismatch repair, poly(ADP)ribosyl transferase, Fos, Jun, and p53 impacts cellular defense.
Conclusions:
- MGMT plays a decisive role in cellular defense against specific genotoxic compounds.
- The genotoxic potential of unrepaired DNA lesions and repair intermediates is significant.
- Transgenic models are powerful for dissecting complex DNA repair and defense pathways.