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. 2016 Jun 9;7(34):54430–54444. doi: 10.18632/oncotarget.9914

Figure 7. Model of temporal regulation of IR-induced clustered damage in human genome.

Figure 7

BER activity at oxidative base lesions at clustered DNA damage could lead to generation of secondary DSBs. Such secondary DSBs generated prior to repair of existing DSBs could lead to loss of genomic sequence. Repair of DSBs in the IR-induced damage cluster is initiated by Ku recruited at DSB, which then assembles the NHEJ complex after recruiting DNA-PKcs. Recruitment of Ku at DSBs also inhibits BER of oxidized bases and AP sites (this study). Early phosphorylation of SAF-A at Ser59 by DNA-PK correlates with transient dissociation of NEIL1 from chromatin to prevent BER initiation. Residual DGs in chromatin are inhibited by Ku while NHEJ occurs. After completion of DSBR, SAF-A is dephosphorylated, relieving Ku inhibition of BER, and restoring NEIL1 levels in chromatin. Ku together with SAF-A thus act as a molecular switch for NHEJ→BER transition.