EPIGENETIC CONTROL OF TOPOISOMERASE1 LESION REPAIR BY A MACRO-HISTONE

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Date
2023-07-31
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Johns Hopkins University
Abstract
Single-stranded DNA lesions (SSLs) are among the most common types of DNA damage. One predominant example for SSLs is Topoisomerase 1 cleavage complex (TOP1cc), which forms as a result of TOP1 activity in response to torsional DNA stress during DNA transactions such as transcription and DNA replication. TOP1ccs are frequently found at transcriptional start sites (TSSs) and can cause DNA damage and chromosome aberrations if not properly resolved. TOP1 inhibitors, such as camptothecin (CPT), are used as a pharmacological tool to trap TOP1cc on DNA, causing excessive DNA damage that kills cancer cells. What promotes efficient TOP1 function at DNA supercoil-forming regions while simultaneously preventing excessive TOP1cc accumulation remains unknown. Given that chromatin plays a central role in regulating the repair of double strand DNA breaks (DSBs), we propose that epigenetic control may similarly be a driver of TOP1cc repair. In previous work, we uncovered the macro-histone variant macroH2A1.1, but not its alternatively spliced macroH2A1.2 isoform, as an interactor of several TOP1cc repair factors. Here, we apply state-of-the-art genome-wide mapping approaches to investigate the relationship between macroH2A1.1 and TOP1 activity. We further relate macroH2A1.1 alternative splicing in cancer TOP1 inhibitor sensitivity across a panel of breast cancer cells with distinct macroH2A1.1 expression levels. Together, my findings point to a role for macroH2A1.1 as an epigenetic regulator of TOP1cc turnover at the TSS and a predictor of therapy responsiveness to TOP1 inhibition.
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Keywords
DNA repair, Topoisomerase 1, macroH2A1.1, Breast cancer, Epigenetics
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