How does NER work?
NER involves several key steps: damage recognition, unwinding of the DNA helix, excision of the damaged strand, synthesis of new DNA to replace the excised section, and ligation to seal the nick. The process is carried out by a complex of proteins, including
XPC,
TFIIH,
XPA,
ERCC1-XPF, and
XPG. Defects in any of these components can hamper the NER process, leading to an accumulation of DNA damage.
Why is NER important in preventing Cancer?
NER plays a vital role in preventing
carcinogenesis by repairing DNA lesions that, if left unchecked, could result in mutations. These mutations may lead to the activation of oncogenes or the inactivation of tumor suppressor genes, thereby initiating cancer development. Therefore, the efficiency of NER is directly linked to the prevention of various types of cancer, including skin cancer, lung cancer, and
bladder cancer.
What happens when NER is defective?
Individuals with defects in NER suffer from disorders such as
Xeroderma Pigmentosum (XP), which is characterized by extreme sensitivity to UV light and a high predisposition to skin cancer. Another condition,
Cockayne Syndrome (CS), involves growth retardation, neurological abnormalities, and premature aging but is not as strongly associated with cancer. Defective NER can also contribute to the accumulation of DNA damage in somatic cells, increasing the risk of sporadic cancers.
How does NER interact with cancer treatments?
NER not only plays a role in cancer prevention but also affects the efficacy of certain cancer treatments. Many chemotherapeutic agents and radiation therapies work by introducing DNA damage that cancer cells cannot repair. If a cancer cell has an intact and highly efficient NER system, it may resist these treatments. Conversely, inhibiting NER can sensitize cancer cells to therapy, making them more susceptible to treatment-induced DNA damage.
Can NER be targeted for cancer therapy?
Given its role in DNA repair, NER represents a potential target for cancer therapy. Inhibitors of NER proteins could be used to enhance the efficacy of DNA-damaging agents. For instance, the inhibition of the
ERCC1-XPF endonuclease complex has shown promise in increasing the sensitivity of cancer cells to platinum-based chemotherapeutics. Additionally, understanding the NER status of a tumor could help tailor personalized treatment strategies, optimizing therapeutic outcomes.
What are the future directions in NER research?
Research in NER continues to evolve, with ongoing studies focusing on understanding the intricate details of the repair mechanism and its regulation. Advanced techniques like
CRISPR-Cas9 are being used to generate models with specific NER defects, which can provide insights into the link between NER and cancer. Furthermore, the development of biomarkers to assess NER activity in tumors could lead to more precise and effective cancer therapies.
Conclusion
Nucleotide Excision Repair is a fundamental process in maintaining genomic integrity and preventing cancer. Defects in NER can lead to an increased risk of various cancers, while its proficient functioning can influence the response to cancer treatments. Understanding and manipulating NER pathways offer promising avenues for enhancing cancer therapy and developing personalized treatment strategies.
