Trends in Pharmacological Sciences
Emerging cancer therapeutic opportunities target DNA-repair systems
Section snippets
Using DNA-repair interference as an approach for cancer treatment
The radioresistance and chemoresistance of tumors are a major obstacle that often leads to the failure of clinical cancer therapy. An important strategy for improving cancer therapy is the development of approaches that are more selective and mechanistic for overcoming tumor resistance 1, 2. Many current non-surgical cancer treatments target the integrity of cellular DNA, which is crucial to cell survival. These agents directly and/or indirectly damage DNA by inducing DNA breaks (e.g. ionizing
AGT in the DR pathway
Chloroethylating and methylating agents attack the O6 position of guanine and form O6-alkylguanine–DNA adducts [11] that trigger cell death (apoptotic or otherwise), regardless of the presence or absence of a functional MMR system [15], by forcing cells into permanent G2–M arrest 16, 17. AGT protects cells from the cytotoxicity of chloroethylating and methylating chemotherapeutics by irreversibly transferring the alkyl group from the adduct to its own cysteine145 residue 18, 19, 20. Notably,
DNA glycosylase, APE1, Polβ and PARP1 in the BER pathway
The BER pathway is required for the removal of alkylated and oxidated bases, which are generated by alkylating agents and oxidative stress, respectively. For single-base damage, DNA glycosylase removes the damaged base and generates an abasic [apurinic–apyrimidinic (AP)] site, AP lyase and APE1 cleave the phosphodiester bonds at the 3′ and 5′ ends of the AP site, respectively, and Polβ, XRCC1 and DNA ligase III (Lig3) are recruited to fill in the gap, with assistance from PAR-synthesized PARP1.
ATM in the HR pathway
DSBs generated directly by ionizing radiation, radiomimetics and ROS, or indirectly by DNA-damaging anticancer drugs such as alkylating agents and topoisomerase inhibitors are repaired by either the HR or the NHEJ pathway. The former pathway relies on the action of ATM, which is a crucial DSB sensor that simultaneously regulates both the HR machineries (Figure 1) and the cell-cycle checkpoints 6, 48. ATM-mutated cells are selectively hypersensitive to DSB inducers, indicating that ATM
DNA-PK in the NHEJ pathway
The NHEJ pathway, which is initiated by DNA-PK activation, is one of the most important DSB-repair pathways in mammalian cells 6, 50 (Figure 1), as evidenced by the observations that DNA-PK-deficient mice are hypersensitive to ionizing radiation and other DSB inducers, whereas increased DNA-PK activity confers radioresistance and chemoresistance to tumor cells 50, 51, 52. DNA-PK comprises the catalytic subunit (DNA-PKcs) and the Ku70 and Ku80 subunits. As with ATM, DNA-PK is a PI3K superfamily
Concluding remarks
Currently, all non-surgical anticancer approaches encounter the problem of tumor resistance. Thus, it is important that the molecular mechanisms of innate and acquired resistance are fully understood and that ways to circumvent both are found. Recent advances in the understanding of DNA-repair mechanisms have identified the disruption of this process as a promising novel modality for overcoming intrinsic and/or acquired resistance, especially to ionizing radiation and DNA-damaging agents.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (30330670) and the Chinese Academy of Sciences (the special scientific research initiation fund for Z-H.M., the winner of the Special Prize of the President Scholarship).
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