Alternative end-joining repair pathways are the ultimate backup for abrogated classical non-homologous end-joining and homologous recombination repair: Implications for the formation of chromosome translocations

• Published in: Mutation research. Genetic toxicology and environmental mutagenesis 2015-11, Vol.793, p.166-175
• Main Authors: Iliakis, George, Murmann, Tamara, Soni, Aashish
• Format: Article
• Language: English
• Subjects: Alternative end-joining; Animals; Chromosome translocations; Chromosomes; Chromosomes - genetics; Chromosomes - radiation effects; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA double strand breaks; DNA End-Joining Repair - radiation effects; G2 Phase - radiation effects; Genomes; Homologous recombination repair; Humans; Ionizing radiation; Non-homologous end-joining; Radiation; Recombinational DNA Repair - radiation effects; Translocation, Genetic
• ISSN: 1383-5718; 1879-3592
• DOI: 10.1016/j.mrgentox.2015.07.001

•Ionizing radiation induces a severe form of DNA damage: double strand break (DSB).•DSBs in higher eukaryotes are processed by HRR, c-NHEJ and alt-EJ.•c-NHEJ and alt-EJ are implicated in the formation of chromosome translocations.•We develop the view that alt-EJ operates as backup to abrogated HRR and c-NHEJ.•We discuss that alt-EJ has major contribution to chromosome translocation formation. DNA double strand breaks (DSB) are the most deleterious lesions for the integrity of the genome, as their misrepair can lead to the formation of chromosome translocations. Cells have evolved two main repair pathways to suppress the formation of these genotoxic lesions: homology-dependent, error-free homologous recombination repair (HRR), and potentially error-prone, classical, DNA-PK-dependent non-homologous end-joining (c-NHEJ). The most salient feature of c-NHEJ, speed, will largely suppress chromosome translocation formation, while sequence alterations at the junction remain possible. It is now widely accepted that when c-NHEJ is inactivated, globally or locally, an alternative form of end-joining (alt-EJ) removes DSBs. Alt-EJ operates with speed and fidelity markedly lower than c-NHEJ, causing thus with higher probability chromosome translocations, and generating more extensive sequence alterations at the junction. Our working hypothesis is that alt-EJ operates as a backup to c-NHEJ. Recent results show that alt-EJ can also backup abrogated HRR in G2 phase cells, again at the cost of elevated formation of chromosome translocations. These observations raise alt-EJ to a global rescuing mechanism operating on ends that have lost their chromatin context in ways that compromise processing by HRR or c-NHEJ. While responsible for eliminating from the genome highly cytotoxic DNA ends, alt-EJ provides this function at the price of increased translocation formation. Here, we analyze recent literature on the mechanisms of chromosome translocation formation and propose a functional hierarchy among DSB processing pathways that makes alt-EJ the global backup pathway. We discuss possible ramifications of this model in cellular DSB management and pathway choice, and analyze its implications in radiation carcinogenesis and the design of novel therapeutic approaches.