Regulation of Repair of Alkylation Damage in Mammalian Genomes

This chapter discusses the current understanding of the molecular basis of the regulation of alkylation damage repair in mammals. Such molecular studies were not possible until the recent success in the cloning of the alkylation repair genes. This chapter first explains the basic mechanisms of repair proteins. The availability of nucleic-acid and antibody probes for many of the alkylation repair genes and proteins, and elucidation of the structure and identification of the regulatory elements of these genes, provide an opportunity for a comprehensive understanding of regulation of alkylation damage repair. The prospect of large-scale production of the human alkylation repair proteins in E. coli for the subsequent determination of their structure by X-ray crystallography and NMR looks quite good. In contrast to inhibition of repair genes at the level of their expression, these genes could also be inactivated in cultured cells by homologous recombination. Starting with mutations in repair genes of pluripotent embryonic stem cells, repair-deficient or repair-negative mice could be generated. Such animals may make excellent models for mutagen, carcinogen, and aging studies.