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.
KeywordsDNA polymerase II; DNA polymerase IV; DNA polymerase V; RecA, LexA, β-clamp; Y-family DNA polymerase; Mutagenesis; Replication Restart; Recombination; SOS response
HISTORICAL OVERVIEWWe now know that TLS is largely facilitated by specialized DNA polymerases that can accommodate bulky adducts in their active sites. Such properties are usually associated with a dramatic decrease in replication fidelity and as a consequence, TLS is often error-prone, leading to an increase in cellular mutagenesis. Significant progress in understanding the
FURTHER READINGFor additional recent reviews on TLS-related topics see references (6,76,101,122,167,173,179,180,203,214).
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Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript molecular mechanisms of TLS have been achieved in the past decade, following the successful purification and biochemical characterization of a number of TLS polymerases. However, prior to the characterization of the highly purified proteins, the pioneering studies on TLS were largely focused on its genetic endpoints, namely its mutagenic consequences. Indeed, the first hint that damage-induced mutagenesis is not a passive process came in the early '50s when Jean Weigle reported that mutagenesis of irradiated bacteriophage λ was significantly enhanced, if the host bacterium had also been irradiated (247). However, it was not until the pioneering studies of Evelyn Witkin working with bacteria that could be killed by UV irradiation, but not mutated, that the concept of damage inducible error-prone translesion DNA synthesis was born (249)(250)(251)253). These ideas were further expanded in 1970 by Miroslav Radman in a privately circulated letter in which he suggested that "SOS replication" ...