DNA interstrand crosslinks (ICLs) are formed by antitumor agents such as cisplatin and nitrogen mustards and inhibit DNA metabolism by covalently linking two strands of DNA. ICLs are processed by multiple complex repair pathways in humans, primarily in the context of replication. All of these pathways share a polymerase step past a partially processed or unhooked ICL as a common element, but the questions of which polymerases are involved and the mechanisms by which they synthesize DNA past ICLs remain poorly understood. We have developed synthetic methods for the generation of site-specific ICLs formed by cisplatin and nitrogen mustards and studied the ability of various polymerases to bypass ICLs. We found that two main factors influenced the efficiency of ICL bypass: the length of the dsDNA flanking the ICL and the structure of the crosslink bridging two bases. Interestingly, we found that the replicative DNA polymerases d and e were able to bypass many of the nitrogen mustard, but not the cisplatin ICLs. Our studies reveal important differences in how DNA polymerases process ICL formed by various antitumor agents and may help inform the use of crosslinking agents in personalized medicine.

Replicative and translesion synthesis DNA polymerases in ICL repair

ACS Fall 2020 Virtual Meeting

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