What is Non-Homologous End Joining (NHEJ)?
Non-Homologous End Joining (NHEJ) is a critical
DNA repair mechanism that fixes double-strand breaks (DSBs) in the DNA. Unlike homologous recombination (HR), NHEJ does not require a homologous template and can operate throughout the cell cycle, making it a versatile but error-prone repair process.
Recognition and binding: Ku70/80 heterodimer rapidly binds to the broken DNA ends.
Bridging the ends: The Ku complex recruits DNA-PKcs, forming a synaptic complex that bridges the DNA ends.
Processing: End processing enzymes like Artemis and polymerases modify the ends to make them compatible for ligation.
Ligation: The XRCC4-Ligase IV complex seals the DNA ends, completing the repair.
Why is NHEJ Important in Cancer?
NHEJ is a double-edged sword in cancer biology. On one hand, it prevents the accumulation of DNA damage that could lead to
genomic instability and cancer progression. On the other hand, its error-prone nature can introduce mutations that contribute to cancer development.
How Do Cancer Cells Exploit NHEJ?
Cancer cells often have upregulated DNA repair pathways, including NHEJ, to survive the high levels of DNA damage they incur. Inhibitors targeting components of the NHEJ pathway, such as DNA-PKcs inhibitors, are being investigated for their potential to sensitize cancer cells to
chemotherapy and radiotherapy.
Therapeutic resistance: Enhanced NHEJ activity can make cancer cells resistant to treatments that induce DNA breaks, such as radiotherapy.
Targeted therapy: Inhibitors of NHEJ components, like DNA-PKcs and Ligase IV, are being developed to increase the efficacy of DNA-damaging agents.
Biomarker potential: Levels of NHEJ activity could serve as biomarkers to predict treatment response and tailor personalized therapies.
Specificity: Developing inhibitors that specifically target cancer cells without affecting normal cells is crucial.
Resistance mechanisms: Cancer cells may develop resistance to NHEJ inhibitors, necessitating combination therapies.
Side effects: Inhibiting a fundamental repair mechanism can lead to off-target effects and toxicity.
Future research aims to better understand the regulation of NHEJ in cancer and develop more effective and specific therapeutic strategies.
Conclusion
Non-Homologous End Joining is a vital DNA repair mechanism with complex roles in cancer. While it helps maintain genomic stability, its error-prone nature can contribute to cancer development and therapeutic resistance. Targeting NHEJ components holds promise for enhancing cancer treatment efficacy, but challenges remain in ensuring specificity and minimizing side effects.
