Necessities in the Processing of DNA Double Strand Breaks and Their Effects on Genomic Instability and Cancer
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....
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/11/1671 |
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| author | George Iliakis Emil Mladenov Veronika Mladenova |
| author_facet | George Iliakis Emil Mladenov Veronika Mladenova |
| author_sort | George Iliakis |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T20:12:52Z |
| format | Article |
| id | doaj.art-9cafd29164ef4be7b5aa26e619ef4908 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T20:12:52Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-9cafd29164ef4be7b5aa26e619ef49082023-08-02T01:35:06ZengMDPI AGCancers2072-66942019-10-011111167110.3390/cancers11111671cancers11111671Necessities in the Processing of DNA Double Strand Breaks and Their Effects on Genomic Instability and CancerGeorge Iliakis0Emil Mladenov1Veronika Mladenova2Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122 Essen, GermanyInstitute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122 Essen, GermanyInstitute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122 Essen, GermanyDouble 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.https://www.mdpi.com/2072-6694/11/11/1671dna repairdouble strand breaks (dsbs)homologous recombination repair (hrr)gene conversion (gc)c-nhejalt-ejsingle strand annealing (ssa)ionizing radiation (ir)complex dsbshigh let radiation |
| spellingShingle | George Iliakis Emil Mladenov Veronika Mladenova Necessities in the Processing of DNA Double Strand Breaks and Their Effects on Genomic Instability and Cancer Cancers dna repair double strand breaks (dsbs) homologous recombination repair (hrr) gene conversion (gc) c-nhej alt-ej single strand annealing (ssa) ionizing radiation (ir) complex dsbs high let radiation |
| title | Necessities in the Processing of DNA Double Strand Breaks and Their Effects on Genomic Instability and Cancer |
| title_full | Necessities in the Processing of DNA Double Strand Breaks and Their Effects on Genomic Instability and Cancer |
| title_fullStr | Necessities in the Processing of DNA Double Strand Breaks and Their Effects on Genomic Instability and Cancer |
| title_full_unstemmed | Necessities in the Processing of DNA Double Strand Breaks and Their Effects on Genomic Instability and Cancer |
| title_short | Necessities in the Processing of DNA Double Strand Breaks and Their Effects on Genomic Instability and Cancer |
| title_sort | necessities in the processing of dna double strand breaks and their effects on genomic instability and cancer |
| topic | dna repair double strand breaks (dsbs) homologous recombination repair (hrr) gene conversion (gc) c-nhej alt-ej single strand annealing (ssa) ionizing radiation (ir) complex dsbs high let radiation |
| url | https://www.mdpi.com/2072-6694/11/11/1671 |
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