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RNA Polymerase II is a Polar Roadblock to a Progressing DNA Fork. | LitMetric

AI Article Synopsis

  • DNA replication and transcription happen at the same time on the same DNA, which can create conflicts between the replisome and RNA polymerase, potentially causing genome instability.
  • Research shows that collisions between RNA polymerase and the replication fork are more harmful when they come from opposite directions (head-on) compared to when they run in the same direction (co-directional), but the exact reasons behind this aren't fully understood.
  • The study found that RNA polymerase binds more stably in head-on conflicts, especially with longer RNA transcripts, which enhances its ability to block replication; an RNA-DNA hybrid forms during this process, creating additional complications for the replication fork but could also help initiate replication on the lagging strand.

Article Abstract

DNA replication and transcription occur simultaneously on the same DNA template, leading to inevitable conflicts between the replisome and RNA polymerase. These conflicts can stall the replication fork and threaten genome stability. Although numerous studies show that head-on conflicts are more detrimental and more prone to promoting R-loop formation than co-directional conflicts, the fundamental cause for the RNA polymerase roadblock polarity remains unclear, and the structure of these R-loops is speculative. In this work, we use a simple model system to address this complex question by examining the Pol II roadblock to a DNA fork advanced via mechanical unzipping to mimic the replisome progression. We found that the Pol II binds more stably to resist removal in the head-on configuration, even with minimal transcript size, demonstrating that the Pol II roadblock has an inherent polarity. However, an elongating Pol II with a long RNA transcript becomes an even more potent and persistent roadblock while retaining the polarity, and the formation of an RNA-DNA hybrid mediates this enhancement. Surprisingly, we discovered that when a Pol II collides with the DNA fork head-on and becomes backtracked, an RNA-DNA hybrid can form on the lagging strand in front of Pol II, creating a topological lock that traps Pol II at the fork. TFIIS facilitates RNA-DNA hybrid removal by severing the connection of Pol II with the hybrid. We further demonstrate that this RNA-DNA hybrid can prime lagging strand replication by T7 DNA polymerase while Pol II is still bound to DNA. Our findings capture basal properties of the interactions of Pol II with a DNA fork, revealing significant implications for transcription-replication conflicts.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482878PMC
http://dx.doi.org/10.1101/2024.10.11.617674DOI Listing

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