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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Taryn M. Kay,
  • James T. Inman,
  • Lucyna Lubkowska,
  • Tung T. Le,
  • Jin Qian,
  • Porter M. Hall,
  • Sahil Batra,
  • Dirk Remus,
  • Dong Wang,
  • Mikhail Kashlev,
  • Michelle D. Wang

摘要

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.