How does Nucleotide Excision Repair (NER) Work?
NER is responsible for removing bulky DNA lesions, such as those caused by UV radiation. The process involves several steps:
1.
Damage recognition: Proteins identify the distorted DNA helix.
2.
Excision: An enzyme complex excises a short single-stranded DNA segment containing the lesion.
3.
Resynthesis: DNA polymerase fills in the gap with the correct nucleotides.
4.
Ligation: DNA ligase seals the new strand into the existing DNA.
What Role Does Base Excision Repair (BER) Play?
BER targets smaller, non-helix-distorting base lesions, such as those caused by oxidation or alkylation. The steps in BER include:
1.
Damage recognition: Glycosylase enzymes detect and remove the damaged bases.
2.
AP site creation: The removal of the base creates an abasic site.
3.
Excision: AP endonuclease cuts the DNA backbone at the abasic site.
4.
Resynthesis and ligation: DNA polymerase and ligase fill in and seal the gap.
What Happens When Excision Repair Fails?
Failures in excision repair pathways can lead to an accumulation of DNA damage, resulting in mutations and chromosomal aberrations. Such genetic alterations are hallmarks of many cancers. For example, defective BER is associated with increased mutation rates in genes critical for cell cycle regulation and apoptosis, potentially leading to cancer.
How Can Excision Repair Mechanisms Be Targeted in Cancer Therapy?
Understanding excision repair pathways allows for the development of targeted cancer therapies. Inhibitors of specific repair proteins can sensitize cancer cells to chemotherapy and radiation by exacerbating DNA damage. For instance,
PARP inhibitors target BER and are particularly effective against cancers with existing DNA repair deficiencies, such as BRCA-mutated breast and ovarian cancers.
Are There Any Current Research Advances in Excision Repair and Cancer?
Ongoing research is exploring the broader potential of targeting DNA repair pathways in cancer therapy. Novel strategies include combination therapies that exploit synthetic lethality, where simultaneous inhibition of multiple repair pathways leads to cancer cell death. Additionally, researchers are investigating biomarkers for predicting patient responses to DNA repair-targeted therapies, aiming to personalize cancer treatment.
Conclusion
Excision repair is a vital defense mechanism against DNA damage and cancer development. Understanding its intricate processes and the consequences of its failure provides valuable insights into cancer biology and opens avenues for innovative therapeutic strategies. By targeting specific elements of excision repair, we can potentially enhance the efficacy of existing treatments and develop new approaches to combat cancer more effectively.
