Necessities in the Processing of DNA Double Strand Breaks and Their Effects on Genomic Instability and Cancer

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.

Carbon Ion Radiobiology

“…The two main DNA DSB repair pathways are non-homologous end joining (NHEJ) and homologous recombination (HR), the latter only active in S and G2-phases of the cell cycle. It has been hypothesized that the production of DSB clusters by densely ionizing radiation triggers alternative, error-prone DNA damage repair (DDR) pathways [ 54 , 55 , 56 ]. A known alternative NHEJ pathway is based on DNA break resection followed by microhomology-mediated recombination [ 57 ].…”

Regulation of Error-Prone DNA Double-Strand Break Repair and Its Impact on Genome Evolution

“…For example, following exposure to ionizing radiation, approximately 80% of IR-induced DSBs in human fibroblasts are repaired by end joining. While most repair is likely carried out by cNHEJ, it is likely that some of the breaks are repaired by alt-EJ, as repair junctions with small insertions or deletions are characteristic of both pathways [61,64,65]. Interestingly, clusters of IR-induced DSBs require alt-EJ for their repair, suggesting that some radiation damage may inhibit repair by cNHEJ [65].…”

Carbon Ion Radiobiology

“…The two main DNA DSB repair pathways are non-homologous end joining (NHEJ) and homologous recombination (HR), the latter only active in S and G2-phases of the cell cycle. It has been hypothesized that the production of DSB clusters by densely ionizing radiation triggers alternative, error-prone DNA damage repair (DDR) pathways [52][53][54]. A known alternative NHEJ pathway is based on DNA break resection followed by microhomology-mediated recombination [55].…”