Replicative bypass

Fig. 4. Possible role of mismatch repair in the cytotoxicity of cisplatin. A) During replicative bypass, a mismatch is incorporated across from the cisplatin-DNA adduct. This compound lesion is bound by the mismatch repair proteins, which cut the DNA on the strand opposite the platinum. Repair synthesis would reproduce the same mismatch, resulting in a futile cycle and possibly the accumulation of DNA strand breaks which would activate apoptosis. B) Alternatively, the mismatch repair complex can recognize the cisplatin-DNA adduct alone and generate a signal that triggers apoptosis.

A number of mechanisms allow a cell to become resistant to cisplatin. The most commonly acknowledged ones include decreased drug uptake [16], increased levels of sulfur-containing macromolecules reacting with cisplatin [17], and increased DNA repair [18]. Increased tolerance to cisplatin adducts may also play a role in the appearance of a resistant phenotype. This is as suggested by data obtained in some ovarian carcinoma cells in which resistance is accompanied by a reduced rate of adduct removal when compared to the sensitive parental cell-line [19]. The molecular mechanism of this phenomenon is unknown but has been correlated with an increased replicative bypass of platinum-DNA adducts. 

Clark, J.M. and Beardsley, G.P. (1989) Template length, sequence context, and 3 -5 exonuclease activity modulate replicative bypass of thymine glycol lesions in vitro. Biochemistry, 28,775-779. 

Kumari, A., Minko, I.G., Harbut, M.B., Finkel, S.E., Goodman, M.F., and Lloyd, R.S. (2008) Replication bypass of interstrand cross-link intermediates by Escherichia coli DNA polymerase IV. 

Tolerance of DNA damage including replicative bypass of template damage with gap formation and translesion DNA synthesis (SOS response). Some of these mechanisms will be considered. 

Haracska, L., Torres-Ramos, G. A., Johnson, R. E., Prakash, S., and Prakash, L. (2004). Opposing effects of ubiquitin conjugation and SUMO modification of PCNA on replicational bypass of DNA lesions in Saccharomyces cerevisiae. Mol. Cell. Biol. 24, 4267-4274. 

Barbour, L., and Xiao, W. (2003). Regulation of alternative replication bypass pathways at stalled replication forks and its effects on genome stability A yeast model. Mutat. Res. 532, 137-155. 

Earley LF, Minko IG, Christov PP, Rizzo CJ, Lloyd RS. Mutagenic spectra arising from replication bypass of the 2,6-diamino-4-hydroxy-N5-methyl formamidopyrimi-dine adduct in primate cells. Chem Res Toxicol. 2013 26 1108—1114. 

Interestingly, during the last couple of years, a whole family of DNA polymerase have been identified and characterized in E. coli, yeast, and mammals (Table II). These enzymes are unique in their ability to bypass DNA base adducts which have lost the ability to base pair and thus are not utilized by standard DNA polymerases. It has been suggested that these replication bypass polymerases allow cell survival by allowing DNA replication even at the cost of introducing mutations. 

Jiang, N. and Taylor, J.-S., In vivo evidence that UV-induced C —> T mutations at dipyrimidine sites could result from the replicative bypass of cis-syn cyclobutane dimers or their deamination products, Biochemistry, 32, 472, 1993. 

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