What is Non-Homologous End Joining (NHEJ)?
Non-Homologous End Joining (NHEJ) is a critical pathway for the repair of
double-strand breaks (DSBs) in DNA. Unlike homologous recombination, which requires a homologous template, NHEJ directly ligates the broken DNA ends without the need for a template. This mechanism is essential for maintaining genomic stability but can be error-prone, leading to the insertion or deletion of nucleotides at the repair site.
How is NHEJ Involved in Cancer?
The integrity of the genome is paramount to cellular function, and the failure to repair DNA breaks correctly can lead to
genomic instability, a hallmark of cancer. Defects in NHEJ can contribute to the accumulation of mutations and chromosomal aberrations, thereby driving
tumorigenesis. Overactive or error-prone NHEJ can result in oncogenic translocations and amplifications, contributing to the development and progression of cancer.
What are the Key Proteins Involved in NHEJ?
Several core proteins play significant roles in the NHEJ pathway.
Ku70/Ku80 heterodimer initially recognizes and binds to DNA ends.
DNA-PKcs (DNA-dependent protein kinase catalytic subunit) is then recruited to form the DNA-PK complex, which processes the DNA ends.
Artemis acts as an endonuclease to trim the DNA ends if necessary. Finally,
XRCC4,
Ligase IV, and
XLF (XRCC4-like factor) work together to ligate the DNA ends, completing the repair process.
How Does NHEJ Contribute to Therapy Resistance?
Cancer cells often exhibit resistance to therapies such as
radiation and
chemotherapy that induce DSBs. Enhanced NHEJ activity can allow these cells to repair therapy-induced DNA damage more effectively, contributing to resistance. For example, overexpression of NHEJ proteins like DNA-PKcs has been associated with poor prognosis and therapy resistance in various cancers.
Can NHEJ be Targeted for Cancer Therapy?
Given its role in repairing DSBs, targeting NHEJ presents a potential therapeutic strategy. Inhibitors of DNA-PKcs and other NHEJ components are being explored to sensitize cancer cells to DNA-damaging agents. For instance,
DNA-PKcs inhibitors can enhance the efficacy of radiation therapy and certain chemotherapeutics by preventing the repair of therapy-induced DNA damage, leading to increased cancer cell death.
What are the Challenges and Future Directions?
One of the major challenges in targeting NHEJ for cancer therapy is the potential for increased toxicity in normal cells, as NHEJ is also crucial for their genomic stability. Therefore, the development of selective inhibitors that preferentially target cancer cells is an area of ongoing research. Additionally, the redundancy and interplay between different DNA repair pathways necessitate a comprehensive understanding of the cancer cell’s repair machinery to develop effective combination therapies.
In conclusion, Non-Homologous End Joining is a vital DNA repair pathway with significant implications in cancer development, progression, and therapy resistance. Understanding the nuances of NHEJ and its interplay with other cellular processes holds promise for developing novel therapeutic strategies to better combat cancer.
