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Polymerase theta: Genome protection through regulated deployment.

Chelsea M Smith1, Gaorav P Gupta2

  • 1Departments of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, United States; Departments of Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, United States.

DNA Repair
|December 27, 2025
PubMed
Summary

DNA Polymerase theta (Polθ) is crucial for DNA repair but can cause genomic instability in cancer. Understanding its regulation is key to targeting cancer therapies.

Keywords:
DNA repairDouble strand break repairMicrohomology mediated end joiningPolymerase theta

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Biology

Background:

  • DNA Polymerase theta (Polθ) is central to theta-mediated end-joining (TMEJ), a DNA double-strand break (DSB) repair pathway.
  • Polθ is conserved in metazoans and plants, indicating a vital role in genome maintenance, though its functions are not fully understood.
  • While POLQ-deficient organisms are viable, they exhibit genomic aberrations, highlighting Polθ's role in preventing instability.

Purpose of the Study:

  • To review the DNA damage contexts requiring Polθ for repair.
  • To explore how Polθ activity is regulated to prevent genome rearrangements in normal cells.
  • To understand the dysregulation of Polθ in cancer and its therapeutic implications.

Main Methods:

  • Literature review of current knowledge on Polθ function and regulation.
  • Synthesis of findings on TMEJ pathway and its role in genome maintenance.
  • Analysis of Polθ's dual role in genome preservation and destabilization.

Main Results:

  • Polθ activity is essential for repairing specific DNA double-strand breaks via TMEJ.
  • Dysregulated Polθ activity in cancer contributes to chromosomal rearrangements through TMEJ hyperactivity.
  • Some cancers with homologous recombination deficiency show dependence on hyperactive TMEJ, making Polθ a therapeutic target.

Conclusions:

  • Polθ's function is context-dependent, acting as both a genome protector and destabilizer.
  • Precise regulatory mechanisms in normal cells restrict Polθ deployment, preventing genomic instability.
  • Loss of these regulatory controls in cancer presents therapeutic opportunities targeting Polθ.