Abstract
Double strand breaks (DSBs) are induced in the DNA following exposure of cells to ionizing radiation (IR) and are highly consequential for genome integrity, requiring highly specialized modes of processing. Erroneous processing of DSBs is a cause of cell death or its transformation to a cancer cell. Four mechanistically distinct pathways have evolved in cells of higher eukaryotes to process DSBs, providing thus multiple options for the damaged cells. The homologous recombination repair (HRR) dependent subway of gene conversion (GC) removes IR-induced DSBs from the genome in an error-free manner. Classical non-homologous end joining (c-NHEJ) removes DSBs with very high speed but is unable to restore the sequence at the generated junction and can catalyze the formation of translocations. Alternative end-joining (alt-EJ) operates on similar principles as c-NHEJ but is slower and more error-prone regarding both sequence preservation and translocation formation. Finally, single strand annealing (SSA) is associated with large deletions and may also form translocations. Thus, the four pathways available for the processing of DSBs are not alternative options producing equivalent outcomes. We discuss the rationale for the evolution of pathways with such divergent properties and fidelities and outline the logic and necessities that govern their engagement. We reason that cells are not free to choose one specific pathway for the processing of a DSB but rather that they engage a pathway by applying the logic of highest fidelity selection, adapted to necessities imposed by the character of the DSB being processed. We introduce DSB clusters as a particularly consequential form of chromatin breakage and review findings suggesting that this form of damage underpins the increased efficacy of high linear energy transfer (LET) radiation modalities. The concepts developed have implications for the protection of humans from radon-induced cancer, as well as the treatment of cancer with radiations of high LET.
Highlights
We developed a rationale for the evolution in vertebrate cells of four mechanistically distinct pathways for the processing of double strand breaks (DSBs), which surprisingly have very different capacities to reconstitute the original genome
We reasoned that in cells, these pathways must be wired in ways allowing first the engagement of the highest fidelity pathway—following an inherent logic aiming at maximizing genomic integrity
We further argued that when cells use a pathway of lower fidelity to process a specific DSB, they do so to address necessities that arise from the suppression of a high-fidelity pathway during processing in the context of chromatin
Summary
Cancer is intricately linked to the formation of chromosomal translocations, one of the most prominent manifestations of genomic instability that underpin the evolution of this disease [1,2,3]. Goal is achieved at goal the cost of events change and destabilize entire genome, as DNA sequence alterations, nucleotide losses, and translocations, such an outcome is clearly preferable to the broken genome that would be left behind when high fidelity processing mechanisms fail in the chromatin environment of the DSB. Along this line of reasoning, unrepaired DSBs, or DNA ends detected after completion of bulk.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call