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DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
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Polymerase stalling during replication, transcription and translation.

Ellen R Edenberg1, Michael Downey1, David Toczyski1

  • 1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.

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Cellular polymerases (DNA polymerase, RNA polymerase, ribosome) stall under stress, triggering specific repair or degradation responses to maintain macromolecular integrity.

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Area of Science:

  • Molecular Biology
  • Cellular Stress Response
  • Biochemistry

Background:

  • Replication, transcription, and translation involve polymerases that can stall due to various cellular stresses.
  • Stalled polymerases pose a threat to macromolecular integrity, necessitating cellular surveillance and response mechanisms.

Purpose of the Study:

  • To review the stresses that cause stalling of DNA polymerase, RNA polymerase, and ribosomes.
  • To elucidate the cellular mechanisms for recognizing stalled polymerases.
  • To describe the subsequent cellular responses to these stalled enzymes.

Main Methods:

  • This review synthesizes existing research on polymerase stalling and cellular responses.
  • It integrates findings from studies on DNA damage, RNA polymerase function, and translation fidelity.
  • The review focuses on the recognition and repair/degradation pathways.

Main Results:

  • Replication stress, often from DNA damage, activates checkpoints for repair or bypass.
  • Transcriptional stress on RNA polymerase, also linked to DNA damage, can initiate transcription-coupled repair or polymerase degradation.
  • Translational stress, due to mRNA or ribosome issues, leads to degradation of mRNA and nascent polypeptides.

Conclusions:

  • Cells possess sophisticated mechanisms to detect and respond to stalled polymerases across replication, transcription, and translation.
  • These responses, including repair and degradation, are crucial for maintaining cellular homeostasis and genomic integrity.