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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:p>High-risk human papillomaviruses (HPVs) activate the Ataxia Telangiectasia Mutated and Ataxia Telangiectasia and Rad3-Related pathways by inducing DNA breaks through the action of viral oncoproteins E6 and E7, which target factors such as topoisomerases. Type I topoisomerases cleave and religate a single strand of DNA, and little is known about how they regulate HPV pathogenesis. The levels of type I topoisomerases, TOP1\u03b1, TOP3\u03b1, and TOP3\u03b2, were all elevated in cells maintaining high-risk HPV genomes, as well as in squamous cell carcinomas. Only TOP1\u03b1 and TOP3\u03b2, but not TOP3\u03b1, bound to HPV genomes and were critical for regulating viral gene transcription and replication with little effect on cell growth. Furthermore, the knockdown of TOP1\u03b1 or TOP3\u03b2 reduced levels of DNA breaks and differentially altered the expression of genes in key pathways. TOP1\u03b1 knockdown reduced the expression of IL6 and activation of the procytokine signaling pathway. In contrast, TOP3\u03b2 targeted EGR3, which regulates growth and differentiation. Finally, TOP1\u03b1 and TOP3\u03b2 differentially regulate the formation of R-loops, which are critical for viral replication. 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