Understanding the mechanobiology of DNA-protein interactions at the single-molecule level

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DNA-protein interactions underpin essential cellular processes such as DNA replication, transcription, and repair, and proteins involved in these processes are targeted in a variety of cancer therapies. Many structures of damaged DNA-protein complexes reveal stark bends in the DNA substrate, suggesting that proteins may exert force on the DNA to bend it during recognition of the damage site, or for catalytic enhancement of the repair. Two such proteins are FEN1 (essential for NER and Okasaki fragment processing) and XPA (essential to NER). Here we will develop novel instrumentation to investigate how force modulates the DNA-protein interactions involved in DNA repair at a fundamental level, and establish high-throughput screening methods which mimic physiological forces on DNA substrates (which naturally arise in cells due to transcription and packaging) to improve hit identification for repair inhibitors.