Mechanism of TOP1-dependent mutations in human cancer

Cancer cells typically have elevated rates of mutation, which promotes metastasis, cancer progression, and therapeutic resistance. TOP1 acts to remove DNA supercoiling during transcription, which creates DNA-protein intermediates called TOP1 cleavage complexes that contribute to transcription-associated mutagenesis (TAM) and produces a signature of 2-to-5bp deletions. However, we identified additional TOP1-induced signatures whose mechanism's contribution to tumorigenesis are unknown. We aim to characterize the TOP1-induced TAM and determine its role in human cancer mutagenesis by measuring mutation rates and producing mutation spectra in a U2OS-derived mutation reporter cell line and whole-genome sequencing.