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    In silico non-homologous end joining following ion induced DNA double strand breaks predicts that repair fidelity depends on break density.

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    Authors
    Henthorn, N
    Warmenhoven, J
    Sotiropoulos, M
    Mackay, Ranald I
    Kirkby, Norman
    Kirkby, Karen J
    Merchant, Michael J
    Affiliation
    Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
    Issue Date
    2018-02-08
    
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    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.
    Citation
    In silico non-homologous end joining following ion induced DNA double strand breaks predicts that repair fidelity depends on break density. 2018, 8(1):2654 Sci Rep
    Journal
    Scientific Reports
    URI
    http://hdl.handle.net/10541/620846
    DOI
    10.1038/s41598-018-21111-8
    PubMed ID
    29422642
    Type
    Article
    Language
    en
    ISSN
    2045-2322
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41598-018-21111-8
    Scopus Count
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