fig1

Figure 1. Schematic view of key DNA damage response pathways. Chemo- and radiotherapies (CT and IR) cause DNA damage, which launches a DNA damage response (DDR) to repair DNA and ensure survival of cancer cells. Current AML standard therapies include cytarabine, anthracyclines, or hypomethylating agents (HMAs) such as azacytidine and decitabine. Cytarabine induces stalled replication forks, leading to DDR activation, which promotes survival via the ATR/CHK1 axis and their downstream targets such as WEE1 in AML cells. Anthracyclines and to some extent HMAs such as azacitidine induce DSBs, leading to DDR activation and repair of DSB by HR and NHEJ, respectively. HR and NHEJ are tightly coordinated by the DDR-initiating master regulators ATM and DNA-PK, respectively, which through various DDR downstream substrates promote delay or block of cell cycle progression and repair of DNA, or TP53-mediated apoptosis if DNA is irreversibly damaged. Hence, in respect of outcome, chemotherapy-induced DNA damage and resultant DDR will confer either survival or apoptosis depending on whether the level of cytotoxicity can overcome the capacity of AML cells to repair DNA. IR: Irradiation/radiotherapy; CT: chemotherapy; DSB: double-strand break; P: phosphorylation; HR: homologous recombination; NHEJ: non-homologous end-joining; ATM: ataxia telangiectasia mutated; ATR: ATR serine/threonine kinase; CHK1: checkpoint kinase 1; CHK2: checkpoint kinase 2; DDR: DNA damage response; DNA-PK: DNA-dependent protein kinase catalytic subunit; DSB: double-strand breaks; HMAs: hypomethylating agents; MRN: Mre11, Rad50, and Nbs1 complex; TP53: tumor protein 53; BRCA1: BRCA1 DNA repair associated; WEE1: WEE1 G2 checkpoint kinase; XLF: XRCC4-like factor; XRCC4: X-ray repair cross complementing 4.