Complex interchanges as a complex function of chromosome organisation.

Area of Science:

• Biophysics
• Radiation Biology
• Cell Biology

Background:

• Understanding the 3D organization of chromatin within the human lymphocyte interphase nucleus is crucial for predicting DNA damage outcomes.
• Existing models often simplify chromosome positioning and dynamics, potentially limiting accurate prediction of complex chromosomal aberrations.

Purpose of the Study:

• To develop and apply a Monte Carlo technique for biophysical modeling of human lymphocyte interphase nucleus structural organization.
• To simulate radiation-induced chromosomal exchange aberrations (CA) by considering chromatin organization, non-random chromosome localization, and loci dynamics.
• To analyze the dose-response relationship for simple and complex CA and compare model predictions with experimental mFISH data.

Main Methods:

• Developed a Monte Carlo technique modeling 46 chromosomes as polymer globules.
• Incorporated different levels of chromatin organization, non-random chromosome localization, and chromosome loci dynamics.
• Simulated intra/interchromosomal contacts and calculated distance-dependent interaction probabilities, including DNA break repair.
• Calculated dose-response for simple and complex CA and compared with mFISH data for human lymphocytes.
• Recalculated CA yields using the alternative SCD model to assess sensitivity to organizational uncertainty.

Main Results:

• The Monte Carlo simulation accurately fitted experimental data for simple chromosomal aberration frequencies.
• Complex chromosomal aberrations were consistently underestimated by the model, even with dense chromosome territory packaging.
• Recalculation using the SCD model also underestimated complex aberration yields.
• The underestimation persisted across different models of nuclear organization.

Conclusions:

• The developed Monte Carlo technique provides a robust framework for modeling chromosome organization and predicting simple radiation-induced aberrations.
• The underestimation of complex aberrations suggests that current models may not fully capture the mechanisms of their formation.
• The movement of damaged loci to common DNA repair factories is proposed as a significant, additional mechanism contributing to complex CA formation.