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  • SO forms adducts via either its


    SO forms adducts via either its epoxide α- or β-position at multiple sites of dA, dC, and dG, and at the N3 position of dT [[5], [6], [7],22,23]. The dG adduct can undergo subsequent depurination, resulting in an abasic site [80], consistent with the finding that endonuclease III is involved in repair of SO-induced damage in human cells [81], and our observation that several BER-associated genes showed TELI responses upon exposure to SO (Fig. 2). In E. coli, elevated SO concentrations promoted acetic W146 receptor formation, membrane permeability, and cell lysis, and a reduction in colony growth and formation, which together are likely the reasons for the more robust stress response to SO in the TELI experiment [82]. It was observed in in vivo bacterial replication assays that DNA containing most SO lesions could be replicated, but DNA containing some of these same lesions could not be replicated with purified replicative DNA polymerases [83,84]. This previous work was carried out prior to the discovery of the biochemical activity of Y-family translesion DNA polymerases; indeed, we observed that deletion of both Y-family polymerases umuDC and dinB sensitizes cells to SO (Fig. 5), suggesting that they play a role in bypass of SO-induced DNA lesions. Deletions of the genes recA, involved in recombination and repair, and ybfE, a gene of unknown function, conferred sensitivity to both CAA and SO. Although recA promoter activity was essentially unchanged upon CAA exposure, there was a low but detectable expression change upon exposure to SO. A similar observation was made for the ruvA promoter, which showed slightly higher expression when exposed to SO than to CAA. One possible reason for the lack of recA promoter activity in TELI is that recA is one of the most abundant proteins in the cell and thus it has been proposed that sufficient RecA is present for some of its functions without induction [85]. Similarly, of two related carcinogens, N-hydroxy-N-2-aminofluorene and acetoxy-N-2-acetylaminofluorene, only the latter induced RecA [86]. Using TELI, similar effects were observed with two genotoxic nanomaterials, nano-silver and nano-TiO2_a, in which nano-silver did not induce RecA whereas nano-TiO-2_a led to robust induction [[33], [34], [35]]. Although the promoters of recA and ruvA are not appreciably activated by exposure to either agent, the roles of recA and ruvA in recombination and DNA repair [60,65,66,87] appear to be important for survival upon exposure to these agents. The strains lacking recA and ybfE showed the largest degree of sensitivity upon exposure to both agents. The critical and multifaceted roles of recA in stress responses are also highlighted by its contributions to survival upon UV- and X-irradation, as well as exposure to a number of antibiotics and other damaging agents [[88], [89], [90], [91], [92], [93]]. Although the function of ybfE is unknown, the decrease in cell survival observed for the mutant strain when exposed to either agent suggests that it plays a key role in DNA damage tolerance; indeed, the ybfE gene is known to be regulated by LexA [74,94] and was upregulated by both CAA and SO.