Gosset DNA (Crosslinking) Overview
DNA crosslinking refers to the formation of covalent bonds between two nucleotides within DNA, either on the same strand (intrastrand) or between opposite strands (interstrand). This process can be triggered by various exogenous agents (such as chemotherapeutic drugs, radiation, or environmental toxins) or endogenous factors. Crosslinks disrupt essential cellular processes such as replication and transcription, leading to cell death. It is a key target in cancer therapy using crosslinking agents that induce apoptosis in rapidly dividing cells. Cells have evolved complex repair pathways for resolving these lesions involving NER, homologous recombination, and base excision repair pathways.
Mechanism of Action
Drugs like cisplatin and nitrogen mustards introduce covalent crosslinks between DNA strands, particularly at guanine residues, which disrupts DNA replication and transcription, leading to cell cycle arrest and apoptosis, especially in rapidly dividing cells such as cancer cells.
Biological Functions
Disease Associations
Safety Considerations
- Off-target effects leading to toxicity in healthy cells
- Development of drug resistance due to increased DNA repair capacity in cancer cells
- Secondary malignancies due to DNA damage in non-cancerous cells
- Myelosuppression
- Nephrotoxicity
Interacting Drugs
Associated Biomarkers
| Biomarker |
|---|
| Levels of DNA adducts |
| Expression of DNA repair proteins (e.g., XPF-ERCC1, BRCA1) |
| Micronuclei formation |