Mechanisms Linking DDR to Tumor Chemosensitivity (IMAGE)
Caption
I. Platinum-based therapies induce DNA inter-strand crosslinks (ICLs), which exacerbate genomic instability and impede DNA replication. In BRCA1/2-deficient tumor cells, the repair of these DNA crosslinks—which relies strictly on the BRCA1/2-mediated homologous recombination repair (HRR) pathway—is compromised, ultimately triggering cell cycle arrest.
II. Alkylating antitumor agents induce DNA alkylation modifications, interfering with DNA repair processes and triggering base mismatches. MMR functional deficiencies lead to ineffective DNA error correction, subsequently inducing MSI and significantly increasing single-nucleotide substitution frequency, thereby suppressing the emergence of chemotherapy resistance.
III. Dysfunction of the ATM/ATR signaling pathways impairs the activation of both ATM-mediated homologous recombination repair (HRR) and non-homologous end joining (NHEJ); this results in the accumulation of DNA double-strand breaks (DSBs) within tumor cells, ultimately potentiating chemotherapy cytotoxicity.
IV. Mutations in DNA damage repair (DDR) genes serve as valuable molecular biomarkers in oncological research. For instance, the HRDetect system predicts therapeutic responses to platinum-based drugs by detecting homologous recombination repair (HRR) deficiencies stemming from BRCA1/2 mutations; similarly, alterations in the RAD51 gene can be used to evaluate the chemosensitivity of liver cancer cells.
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Anqi Lin, Jinyue He
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