Fig. 1
From: The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment
Causes of the DNA damage response and replication stress response. The progression of replication forks faces frequent obstacles, such as RS due to various factors, including a reduced dNTPs pool, b repetitive sequence-composed DNA fragile sites, c TRCs and associated R-loop formation. Additionally, DNA undergoes constantly intrinsic and extrinsic assaults leading to the DDR. Intrinsic assaults include disabled DNA repair, nucleotide stochastic errors, and intracellular metabolite (e.g. ROS) activity, while extrinsic assaults include UV, IR, and anticancer drugs. Several bulky DNA adducts, such as DNA‒protein adducts, DNA intrastrand cross-links and DNA interstrand cross-links, are common causes of DDR and RS. The numbers on the right side represent: 1. DNA‒protein adducts, 2. bulky DNA adducts, 3. DNA intrastrand cross-links, 4. DNA interstrand crosslinks, 5. Base deletion, 6. DNA mismatches, 7. Base insertion, 8. Abasic sites, 9. Single-strand DNA breaks, 10. Double-strand DNA breaks. dNTPs Deoxyribonucleoside triphosphates; TRCs Transcription–replication conflicts; ROS Reactive oxygen species; UV Ultraviolet; IR Ionizing radiation; NER Nucleotide excision repair; FA pathway Fanconi anemia pathway; MMR Mismatch repair; BER Base excision repair; SSBR Single-strand break repair; HR Homologous recombination; NHEJ Nonhomologous end joining