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The genome experiences constant tension and torsion inside our cells due to the activity of proteins that loop, compact, and untwist DNA. A recent study led by scientists at Clemson University provides new insights into how these mechanical forces impact the transcription process. In this critical step, RNA polymerase (RNAP) synthesizes RNA from DNA.
Laura Finzi, endowed chair in medical biophysics at Clemson, and her team explored how mechanical force influences gene transcription, focusing on RNAP’s interaction with DNA. “There are a lot of mechanical forces at play all the time that we never consider, we have very little knowledge of, and they’re not talked about in textbooks,” Finzi noted.
New Insights into the Transcription Process
Transcription is initiated when RNAP binds to a promoter sequence on DNA, and then reads the genetic code to synthesize messenger RNA (mRNA). Traditionally, it’s thought that RNAP detaches from the DNA at a terminator sequence, releasing the mRNA product. However, Finzi’s research has uncovered an alternative pathway in which mechanical forces can drive RNAP to reinitiate transcription without fully detaching.
The team used magnetic tweezers to apply force along the DNA strand, showing that RNAP can be pulled backward or forward after reaching a terminator. This sliding allows RNAP to engage another promoter and begin a new transcription cycle. These subunits “allow it to stay on track, flip around, and grab the other strand of the DNA double helix where another promoter might be,” Finzi said. The force-driven recycling mechanism suggests that gene segments may be transcribed multiple times, depending on the direction of the force applied.
Role of Alpha Subunits
An essential element of this force-directed mechanism involves the C-terminal domain of the RNAP alpha subunit. These subunits are responsible for recognizing promoter sequences opposite the direction in which RNAP slides along the DNA. When the alpha subunits are deleted, RNAP cannot flip and engage with oppositely oriented promoters. This demonstrates the importance of these subunits in maintaining RNAP's ability to continue transcription under mechanical force.
This finding indicates a possible regulatory mechanism that could alter the expression levels of adjacent genes based on physical forces acting on the DNA. The research team demonstrated that the sliding mechanism could play a role in modulating gene transcription depending on the abundance of mechanical forces in the cell.
Potential Future Applications
Although this study focuses on bacterial RNA polymerase, Finzi suggests that these findings may also be applicable to higher organisms. Further research could uncover regions in the genome where recycling of RNAP is more frequent. “My hope is that one day we will have a spatio-temporal map of forces acting on the genome at various times during the life cycle of various types of cells in our organism,” she said. “Our research highlighting the effect of forces on the probability of repetitive transcription may then help predicting and plotting, in a heat map sort of way, the different levels of transcription of different genes.”
Publication Details
Qian, J., Wang, B., Artsimovitch, I. et al. Force and the α-C-terminal domains bias RNA polymerase recycling. Nat Commun 15, 7520 (2024). https://doi.org/10.1038/s41467-024-51603-3
Laura Finzi, endowed chair in medical biophysics at Clemson, and her team explored how mechanical force influences gene transcription, focusing on RNAP’s interaction with DNA. “There are a lot of mechanical forces at play all the time that we never consider, we have very little knowledge of, and they’re not talked about in textbooks,” Finzi noted.
New Insights into the Transcription Process
Transcription is initiated when RNAP binds to a promoter sequence on DNA, and then reads the genetic code to synthesize messenger RNA (mRNA). Traditionally, it’s thought that RNAP detaches from the DNA at a terminator sequence, releasing the mRNA product. However, Finzi’s research has uncovered an alternative pathway in which mechanical forces can drive RNAP to reinitiate transcription without fully detaching.
The team used magnetic tweezers to apply force along the DNA strand, showing that RNAP can be pulled backward or forward after reaching a terminator. This sliding allows RNAP to engage another promoter and begin a new transcription cycle. These subunits “allow it to stay on track, flip around, and grab the other strand of the DNA double helix where another promoter might be,” Finzi said. The force-driven recycling mechanism suggests that gene segments may be transcribed multiple times, depending on the direction of the force applied.
Role of Alpha Subunits
An essential element of this force-directed mechanism involves the C-terminal domain of the RNAP alpha subunit. These subunits are responsible for recognizing promoter sequences opposite the direction in which RNAP slides along the DNA. When the alpha subunits are deleted, RNAP cannot flip and engage with oppositely oriented promoters. This demonstrates the importance of these subunits in maintaining RNAP's ability to continue transcription under mechanical force.
This finding indicates a possible regulatory mechanism that could alter the expression levels of adjacent genes based on physical forces acting on the DNA. The research team demonstrated that the sliding mechanism could play a role in modulating gene transcription depending on the abundance of mechanical forces in the cell.
Potential Future Applications
Although this study focuses on bacterial RNA polymerase, Finzi suggests that these findings may also be applicable to higher organisms. Further research could uncover regions in the genome where recycling of RNAP is more frequent. “My hope is that one day we will have a spatio-temporal map of forces acting on the genome at various times during the life cycle of various types of cells in our organism,” she said. “Our research highlighting the effect of forces on the probability of repetitive transcription may then help predicting and plotting, in a heat map sort of way, the different levels of transcription of different genes.”
Publication Details
Qian, J., Wang, B., Artsimovitch, I. et al. Force and the α-C-terminal domains bias RNA polymerase recycling. Nat Commun 15, 7520 (2024). https://doi.org/10.1038/s41467-024-51603-3