In Silico Non-Homologous End Joining Following Ion Induced DNA Double Strand Breaks Predicts That Repair Fidelity Depends on Break Density

Nicholas Henthorn (Lead), John Warmenhoven (Lead), Marios Sotiropoulos, Ranald Mackay, Norman Kirkby, Karen Kirkby, Michael Merchant

Research output: Contribution to journalArticlepeer-review

Abstract

This work uses Monte Carlo simulations to investigate the dependence of residual and misrepaired double strand breaks (DSBs) at 24 hours on the initial damage pattern created during ion therapy. We present results from a nanometric DNA damage simulation coupled to a mechanistic model of Non-Homologous End Joining, capable of predicting the position, complexity, and repair of DSBs. The initial damage pattern is scored by calculating the average number of DSBs within 70 nm from every DSB. We show that this local DSB density, referred to as the cluster density, can linearly predict misrepair regardless of ion species. The models predict that the fraction of residual DSBs is constant, with 7.3% of DSBs left unrepaired following 24 hours of repair. Through simulation over a range of doses and linear energy transfer (LET) we derive simple correlations capable of predicting residual and misrepaired DSBs. These equations are applicable to ion therapy treatment planning where both dose and LET are scored. This is demonstrated by applying the correlations to an example of a clinical proton spread out Bragg peak. Here we see a considerable biological effect past the distal edge, dominated by residual DSBs.
Original languageEnglish
Article number2654
Pages (from-to)2654
JournalScientific Reports
Volume8
Issue number1
Early online date8 Feb 2018
DOIs
Publication statusPublished - 8 Feb 2018

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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