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Related Concept Videos

DNA Topoisomerases02:02

DNA Topoisomerases

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Topoisomerases are enzymes that relax overwound DNA molecules during various cell processes, including DNA replication and transcription. These enzymes regulate positive and negative DNA supercoiling without changing the nucleotide sequence. DNA overwinding in a clockwise direction results in positively supercoiled DNA, whereas underwinding in a counterclockwise direction produces negatively supercoiled DNA.
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Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
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DNA Distortion and Damage
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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
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Author Spotlight: Combining Proximity Ligand Assay with Gamma-H2AX Staining to Characterize Protein Interactions in DNA Damage Response
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Ultra-high dose rate dependent modeling of plasmid DNA damage with TOPAS-nBio.

Thongchai A M Masilela1, J Naoki D-Kondo1, Wook-Geun Shin2

  • 1Department of Radiation Oncology, University of California San Francisco, San Francisco, CA 94115, United States of America.

Physics in Medicine and Biology
|April 21, 2026
PubMed
Summary

FLASH radiotherapy (ultra-high dose rate) may reduce DNA damage in normal tissues by minimizing intertrack effects at low scavenging capacities. This simulation explains varied experimental results in plasmid DNA damage studies.

Keywords:
DNA damageFLASHMonte Carlo modelingTOPAS-nBioplasmids

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Area of Science:

  • Medical Physics
  • Radiation Biology
  • Computational Biology

Background:

  • FLASH radiotherapy (FLASH-RT) uses ultra-high dose rates (UHDR) to potentially spare normal tissues while controlling tumors.
  • The mechanism for normal tissue sparing in FLASH-RT, possibly reduced DNA damage, is not fully understood.
  • Plasmid assays are used to study DNA damage but yield varied results, necessitating advanced modeling.

Purpose of the Study:

  • To develop and validate a Monte Carlo (MC) model for plasmid DNA damage at UHDR using TOPAS-nBio.
  • To investigate the influence of dose rate and scavenging capacity on DNA damage, specifically single-strand breaks (SSBs) and double-strand breaks (DSBs).
  • To compare simulation results with experimental data to understand discrepancies in plasmid assay findings.

Main Methods:

  • Modeled radiolysis of pUC19 plasmid DNA in aqueous solution using TOPAS-nBio.
  • Simulated 100 Gy dose deposition at conventional (CONV) and UHDR (2 x 10^7 Gy/s) using 225 kVp X-rays.
  • Evaluated two models: one without DNA repair and one incorporating chemical repair via WR-1065 to simulate oxygen competition.

Main Results:

  • The MC model accurately reproduced experimental SSB yields at CONV dose rates within 2% uncertainty.
  • At low scavenging capacities, UHDR resulted in significant reductions in SSBs (54.7%) and DSBs (73.5%) compared to CONV.
  • At biologically relevant scavenging capacities, no significant difference in DNA damage or chemical repair was observed between UHDR and CONV.

Conclusions:

  • The simulated reduction in DNA damage at low scavenging capacities is attributed to the intertrack effect.
  • No significant difference in DNA damage is predicted at low DNA concentrations and cell-like scavenging capacities between UHDR and CONV.
  • The findings suggest that intertrack effects are crucial for understanding FLASH-RT's normal tissue sparing at low scavenging conditions.