Increased Resection at DSBs in G2-Phase Is a Unique Phenotype Associated with DNA-PKcs Defects That Is Not Shared by Other Factors of c-NHEJ
| Autor: | Huaping Xiao, Fanghua Li, Emil Mladenov, Aashish Soni, Veronika Mladenova, Bing Pan, Rositsa Dueva, Martin Stuschke, Beate Timmermann, George Iliakis |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Medizinische Fakultät » Universitätsklinikum Essen » Institut für Medizinische Strahlenbiologie
General Medicine ddc:610 Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Strahlentherapie Medizinische Fakultät » Universitätsklinikum Essen » Institut für Physiologie DSB repair DNA-PKcs c-NHEJ DNA end-resection ionizing radiation Medizinische Fakultät » Universitätsklinikum Essen » Westdeutsches Protonentherapiezentrum (WPE) DSB repair -- DNA-PKcs -- c-NHEJ -- DNA end-resection -- ionizing radiation |
| Zdroj: | Cells; Volume 11; Issue 13; Pages: 2099 |
| Popis: | The load of DNA double-strand breaks (DSBs) induced in the genome of higher eukaryotes by different doses of ionizing radiation (IR) is a key determinant of DSB repair pathway choice, with homologous recombination (HR) and ATR substantially gaining ground at doses below 0.5 Gy. Increased resection and HR engagement with decreasing DSB-load generate a conundrum in a classical non-homologous end-joining (c-NHEJ)-dominated cell and suggest a mechanism adaptively facilitating resection. We report that ablation of DNA-PKcs causes hyper-resection, implicating DNA-PK in the underpinning mechanism. However, hyper-resection in DNA-PKcs-deficient cells can also be an indirect consequence of their c-NHEJ defect. Here, we report that all tested DNA-PKcs mutants show hyper-resection, while mutants with defects in all other factors of c-NHEJ fail to do so. This result rules out the model of c-NHEJ versus HR competition and the passive shift from c-NHEJ to HR as the causes of the increased resection and suggests the integration of DNA-PKcs into resection regulation. We develop a model, compatible with the results of others, which integrates DNA-PKcs into resection regulation and HR for a subset of DSBs. For these DSBs, we propose that the kinase remains at the break site, rather than the commonly assumed autophosphorylation-mediated removal from DNA ends. |
| Databáze: | OpenAIRE |
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