Journal
JOURNAL OF CELL SCIENCE
Volume 125, Issue 7, Pages 1633-1643Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.094748
Keywords
DNA damage tolerance; Translesion synthesis; Homologous recombination; Mutagenesis
Categories
Funding
- Medical Research Council
- Association for International Cancer Research
- The Fanconi Anemia Research Fund
- MRC [MC_U105178808] Funding Source: UKRI
- Medical Research Council [MC_U105178808] Funding Source: researchfish
- Worldwide Cancer Research [11-0514] Funding Source: researchfish
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Cells 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.
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