NDLI: Increased Resection at DSBs in $G_{2}$-Phase Is a Unique Phenotype Associated with DNA-PKcs Defects That Is Not Shared by Other Factors of c-NHEJ

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Increased Resection at DSBs in $G_{2}$-Phase Is a Unique Phenotype Associated with DNA-PKcs Defects That Is Not Shared by Other Factors of c-NHEJ

Content Provider	MDPI
Author	Xiao, Huaping Li, Fang Hua Mladenov, Emil Soni, Aashish Mladenova, Veronika Pan, Bing Dueva, Rositsa Stuschke, Martin Timmermann, Beate Iliakis, George
Copyright Year	2022
Description	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.
Starting Page	2099
e-ISSN	20734409
DOI	10.3390/cells11132099
Journal	Cells
Issue Number	13
Volume Number	11
Language	English
Publisher	MDPI
Publisher Date	2022-07-02
Access Restriction	Open
Subject Keyword	Cells Cell Biology Dsb Repair Dna-pkcs C-nhej Dna End-resection Ionizing Radiation
Content Type	Text
Resource Type	Article

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