Competition, collaboration and coordination – determining how cells bypass DNA damage

Abstract

SummaryCells must overcome replication blocks that might otherwise lead to genomic instability or cell death. Classical genetic experiments have identified a series of mechanisms that cells use to replicate damaged DNA: translesion synthesis, template switching and homologous recombination. In translesion synthesis, DNA lesions are replicated directly by specialised DNA polymerases, a potentially error-prone approach. Template switching and homologous recombination use an alternative undamaged template to allow the replicative polymerases to bypass DNA lesions and, hence, are generally error free. Classically, these pathways have been viewed as alternatives, competing to ensure replication of damaged DNA templates is completed. However, this view of a series of static pathways has been blurred by recent work using a combination of genetic approaches and methodology for examining the physical intermediates of bypass reactions. These studies have revealed a much more dynamic interaction between the pathways than was initially appreciated. In this Commentary, I argue that it might be more helpful to start thinking of lesion-bypass mechanisms in terms of a series of dynamically assembled 'modules', often comprising factors from different classical pathways, whose deployment is crucially dependent on the context in which the bypass event takes place.

Translesion DNA Synthesis and Mutagenesis in Eukaryotes

“…These modifications are principally linked to recombinational modes of damage bypass. Nonetheless, it is clear that there is complex cross-talk between the mechanisms that control recombination and TLS (Sale 2012). For example, the E3 ligase responsible for PCNA polyubiquitination is also required for efficient TLS in both S. cerevisiae (Pages et al 2008) and Schizosaccharomyces pombe (Coulon et al 2010).…”

“…It seems likely, based on some of the parameters discussed above, that the lesion itself plays a role in determining which polymerase is ultimately employed, even if this is simply a question of which enzyme can perform the reaction in the most straightforward manner, seen for example in the replication of CPDs by Pol h. It may also be that the context in which the lesion is found limits the options for its bypass (Sale 2012). …”

DNA Damage Tolerance Pathway Choice Through Uls1 Modulation of Srs2 SUMOylation in Saccharomyces cerevisiae

“…This demonstrates the importance of both DDT-and HR-mediated pathways in coping with various forms of replication stress, although their relative contributions and interactions have not been well established (Unk et al 2010;Sale 2012;Symington et al 2014).…”

Lesion-Induced Mutation in the Hyperthermophilic Archaeon Sulfolobus acidocaldarius and Its Avoidance by the Y-Family DNA Polymerase Dbh

“…Lesion bypass, also termed "damage tolerance," can follow various alternatives, which are broadly distinguished as error-free vs. error-prone (Lehmann et al 2007). The error-free pathways generally use recombinationassociated functions to pair a strand, newly synthesized on intact template, to the damaged DNA strand; the mechanisms for this include transient reversal of the replication fork and strand exchange at gaps left behind the fork (Sale 2012). These mechanisms bypass lesions accurately, although they can promote other forms of genetic instability, such as ectopic recombination between dispersed repeats (Izhar et al 2013).…”