fig1

Figure 1. DDR signaling. Ionizing radiation and genotoxic chemotherapy create single- and double-strand DNA damage including DSBs that activate three PIKKs: DNA-PK, ATM, and ATR. Single-strand breaks and base damage, if not repaired by base excision repair (BER), block replication, which produces ssDNA when the replisome decouples from the MCM helicase or stalled forks are cleaved to produce DSBs, which, along with frank DSBs, are resected to 3’ single-stranded tails that are coated by RPA. This activates ATR to signal checkpoint responses through Chk1 and p53. Non-resected DSB ends are bound by the Ku70/Ku80 heterodimer, which recruits and activates DNA-PKcs in the DNA-PK holoenzyme, LigIV/XRCC4 ligates DNA ends to effect NHEJ. The competing HR pathway initiates with limited DSB end resection by MRE11/RAD50/NBS1 (MRN), more extensive resection by Exo1 and Dna2, and RAD51 binding to ssDNA (mediated by BRCA1, BRCA2, and other proteins) to yield the RAD51-ssDNA nucleoprotein filament that effects HR. DDR: DNA damage response; DSBs: DNA double-strand breaks