Inducible SOS Response System of DNA Repair and Mutagenesis in Escherichia coli
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A large fraction of human cancers arise from exposure to chemicals, although radiation, oxidation, and genetic factors play critical roles as well. DNA damage by these agents in a cell is an important first step in the process of carcinogenesis. DNA repair processes have evolved to repair these damages. However, replication of damaged DNA may occur frequently prior to repair, resulting in gene mutations and generation of altered proteins. Mutations in an oncogene, a tumor-suppressor gene, or a gene that controls the cell cycle give rise to a clonal cell population with an advantage in proliferation. The complex process of carcinogenesis includes many such events, but has been generally considered to be comprised of the three main stages known as initiation, promotion, and progression, which ultimately give rise to the induction of human cancer.
DNA damage is a constant threat to cells, causing cytotoxicity as well as inducing genetic alterations. The steady-state abundance of DNA lesions in a cell is minimized by a variety of DNA repair mechanisms, including DNA strand break repair, mismatch repair, nucleotide excision repair, base excision repair, and ribonucleotide excision repair. The efficiencies and mechanisms by which these pathways remove damage from chromosomes have been primarily characterized by investigating the processing of lesions at defined genomic loci, among bulk genomic DNA, on episomal DNA constructs, or using in vitro substrates. However, the structure of a chromosome is heterogeneous, consisting of heavily protein-bound heterochromatic regions, open regulatory regions, actively transcribed genes, and even areas of transient single stranded DNA. Consequently, DNA repair pathways function in a much more diverse set of chromosomal contexts than can be readily assessed using previous methods. Recent efforts to develop whole genome maps of DNA damage, repair processes, and even mutations promise to greatly expand our understanding of DNA repair and mutagenesis. Here we review the current efforts to utilize whole genome maps of DNA damage and mutation to understand how different chromosomal contexts affect DNA excision repair pathways.