Translesion DNA Synthesis

Abstract

All living organisms are continually exposed to agents that damage their DNA, which threatens the integrity of their genome. As a consequence, cells are equipped with a plethora of DNA repair enzymes to remove the damaged DNA. Unfortunately, situations nevertheless arise where lesions persist, and these lesions block the progression of the cell’s replicase. Under these situations, cells are forced to choose between recombination-mediated “damage avoidance” pathways, or use a specialized DNA polymerase (pol) to traverse the blocking lesion. The latter process is referred to as Translesion DNA Synthesis (TLS). As inferred by its name, TLS not only results in bases being (mis)incorporated opposite DNA lesions, but also downstream of the replicase-blocking lesion, so as to ensure continued genome duplication and cell survival. Escherichia coli and Salmonella typhimurium possess five DNA polymerases, and while all have been shown to facilitate TLS under certain experimental conditions, it is clear that the LexA-regulated and damage-inducible pols II, IV and V perform the vast majority of TLS under physiological conditions. Pol V can traverse a wide range of DNA lesions and performs the bulk of mutagenic TLS, whereas pol II and pol IV appear to be more specialized TLS polymerases.

The antioxidant drug N-acetylcysteine abolishes SOS-mediated mutagenesis produced by fluoroquinolones in bacteria

“…The quinolonemediated increase in mutagenesis has been attributed to the activity of TLS DNApolymerases, whose transcription is induced as part of the SOS response (9,53). However, our results and previous studies strongly suggest that high levels of ROS are also mutagenic (17)(18)(19).…”

“…However, when DNA damage is persistent, the errorprone DNA translesion synthesis (TLS) takes place. In Escherichia coli, TLS is accomplished by the specialized DNA polymerases Pol II, Pol IV and Pol V, encoded respectively by the polB, dinB and umuDC genes (9). TLS polymerases are able to replicate heavily damaged DNA but do so at the cost of a reduced fidelity, therefore increasing mutagenesis (5).…”

“…TLS is a process by which heavily damaged DNA can be replicated at the cost of a reduced fidelity. In Escherichia coli, TLS is accomplished by the specialized DNA polymerases Pol II, Pol IV and Pol V, encoded respectively by the polB, dinB and umuDC genes (Vaisman et al 2012). Notably, RecA-mediated recombination is also induced by fluoroquinolone antibiotics (López et al 2007).…”

The SOS system: A complex and tightly regulated response to DNA damage

“…DNA Pol V, the second error-prone polymerase is expressed at almost an undetectable level (Woodgate and Ennis, 1991). Participation of these accessory polymerases in E. coli chromosome replication and their effect on the fidelity of DNA replication and ability to copy damaged DNA was reviewed in (Walsh et al, 2011;Fijalkowska et al, 2012;Vaisman et al, 2012a;Goodman et al, 2016;Jaszczur et al, 2016;Henrikus et al, 2018b). Upon DNA damage the level of three TLS DNA polymerases, DNA polymerase II, DNA polymerase IV, and DNA polymerase V is elevated, as part of the E. coli inducible SOS response (Napolitano et al, 2000).…”

Mutation Landscape of Acquired Cross-Resistance to Glycopeptide and β-Lactam Antibiotics in Enterococcus faecium

“…A mutation leading to substitution D 187 N in a putative DNA polymerase was detected in mutant M4. In E. coli, the closest homologue is the translesion error-prone DNA polymerase V subunit, which causes increased mutagenesis by promoting translesion synthesis of DNA damaged by UV or chemicals (19). Impaired activity is predicted to lead to a reduction in the mutation rate and might therefore act as a suppressor of the mutL mutation detected in M2.…”