Role of DNA Repair in Cisplatin-Induced Lesion When DNA repair enzymes encounter cis-DNA adducts, they start a cascade awakening overall cellular response to lessen the damage caused by such bulky lesion forms . As an alkylating agent widely used chemotherapeutic drug, cisplatin primarily forms intrastrand crosslinks between two guanines in close proximity to each other (38), leading to severe distortion of the DNA helix and impacting its functions. It can create replication fork stalling and finally double-strand breaks (DSBs) formation if it is not repaired properly.DNA Repair (ad)
Recognition of these adducts by the specialized repair proteins initiates the DNA repair process. While the bulk of cisplatin-induced damage is repaired via the nucleotide excision repair(NER) pathway. In the pathway, several proteins that are involved in damage recognition and unwinding of the DNA helix for excision of the damaged nucleotides work together including XPC and TFIIX. After removal, DNA polymerases then are engaged to generate new DNA strands, completing the process of genetic material repair.
Besides NER, cells may also use translesion synthesis (TLS) to bypass lesions caused by cisplatin. This process allows DNA polymerases to synthesize through lesions, at the expense of an increased risk of introducing mutations. Interaction between these repair pathways is critical; if this system is overactive, it could promote cisplatin resistance seen in a number of tumors, as cells can adapt to survive even with DNA damage.
Furthermore, the cisplatin-induced cellular response is not restricted to just repair pathways in DNA damage. And it includes the signaling pathways that, if the damage is unrepairable, can result in either cell cycle arrest or apoptosis. For example, the activation of p53 can drive apoptosis when DNA damage is excessive. These complex iron-regulatory processes provide insights into how cells respond to chemotherapy, and could reveal targets for bypassing drug resistance.
