RNA polymerase II is a polar roadblock to a progressing DNA fork

Taryn M. Kay, James T. Inman, Lucyna Lubkowska, Tung T. Le, Jin Qian, Porter M. Hall, Sahil Batra, Dirk Remus, Dong Wang, Mikhail Kashlev and Michelle D. Wang ()
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Taryn M. Kay: Cornell University
James T. Inman: Cornell University
Lucyna Lubkowska: National Cancer Institute
Tung T. Le: Cornell University
Jin Qian: Cornell University
Porter M. Hall: Cornell University
Sahil Batra: Memorial Sloan Kettering Cancer Center
Dirk Remus: Memorial Sloan Kettering Cancer Center
Dong Wang: University of California San Diego
Mikhail Kashlev: National Cancer Institute
Michelle D. Wang: Cornell University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Transcription–replication conflicts threaten genome stability. Although head-on conflicts are more detrimental and prone to R-loop formation than co-directional conflicts, the cause of this RNA polymerase roadblock polarity remains unclear, and proposed structures of these R-loops are speculative. Here, we examine the Pol II roadblock to a DNA fork advanced by mechanical unzipping to mimic replisome progression. We found that a head-on Pol II with a minimal transcript resists disruption more strongly, revealing inherent polarity. Moreover, an elongating Pol II with a long RNA transcript becomes an even more potent roadblock, mediated by RNA–DNA hybrid formation. Surprisingly, when a Pol II collides with the DNA fork head-on and becomes backtracked, a hybrid can form in front of Pol II, creating a topological lock that traps Pol II at the fork. Our findings capture the basal properties of Pol II interactions with a DNA fork, revealing significant implications for transcription–replication conflicts.

Date: 2025
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DOI: 10.1038/s41467-025-63662-1

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