{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:45:41Z","timestamp":1790790341530,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T00:00:00Z","timestamp":1695772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["aapm.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Medical Physics"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Cancer is a highly heterogeneous disease, driven by frequent genetic alterations which have significant effects on radiosensitivity. However, radiotherapy for a given cancer type is typically given with a standard dose determined from population\u2010level trials. As a result, a proportion of patients are under\u2010 or over\u2010dosed, reducing the clinical benefit of radiotherapy. Biological optimization would not only allow individual dose prescription but also a more efficient allocation of limited resources, such as proton and carbon ion therapy.<\/jats:p><jats:p>Proton and ion radiotherapy offer an advantage over photons due to their elevated Relative Biological Effectiveness (RBE) resulting from their elevated Linear Energy Transfer (LET). Despite significant interest in optimizing LET by tailoring radiotherapy plans, RBE's genetic dependence remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Purpose<\/jats:title><jats:p>The aim of this study is to better define the RBE\/LET relationship in a panel of cell lines with different defects in DSB repair pathways, but otherwise identical biological features and genetic background to isolate these effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Normal human cells (RPE1), genetically modified to introduce defects in DNA double\u2010strand break (DSB) repair genes, ATM, BRCA1, DCLRE1C, LIG4, PRKDC and TP53, were used to map the RBE\u2010LET relationship. Cell survival was measured with clonogenic assays after exposure to photons, protons (LET 1 and 12\u00a0keV\/\u00b5m) and alpha particles (129\u00a0keV\/\u00b5m). Gene knockout sensitizer enhancement ratio (SER) values were calculated as the ratio of the mean inactivation dose (MID) of wild\u2010type cells to repair\u2010deficient cells, and RBE values were calculated as the ratio of the MID of X\u2010ray and particle irradiated cells. 53BP1 foci were used to quantify radiation\u2010induced DSBs and their repair following irradiation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Deletion of NHEJ genes had the greatest impact on photon sensitivity (ATM<jats:sup>\u2212\/\u2212<\/jats:sup> SER\u00a0=\u00a02.0 and Lig4<jats:sup>\u2212\/\u2212<\/jats:sup> SER\u00a0=\u00a01.8), with genes associated with HR having smaller effects (BRCA1<jats:sup>\u2212\/\u2212<\/jats:sup> SER\u00a0=\u00a01.2). Wild\u2010type cells showed RBEs of 1.1, 1.3, 5.0 for low\u2010 and high\u2010LET protons and alpha particles respectively. SERs for different genes were independent of LET, apart from NHEJ knockouts which proved to be markedly hypersensitive across all tested LETs. Due to this hypersensitivity, the impact of high LET was reduced in cell models lacking the NHEJ repair pathway. HR\u2010defective cells had moderately increased sensitivity across all tested LETs, but, notably, the contribution of HR pathway to survival appeared independent of LET. Analysis of 53BP1 foci shows that NHEJ\u2010defective cells had the least DSB repair capacity after low LET exposure, and no visible repair after high LET exposure. HR\u2010defective cells also had slower repair kinetics, but the impact of HR defects is not as severe as NHEJ defects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>DSB repair defects, particularly in NHEJ, conferred significant radiosensitivity across all LETs. This sensitization appeared independent of LET, suggesting that the contribution of different DNA repair pathways to survival does not depend on radiation quality.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mp.16764","type":"journal-article","created":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T11:43:41Z","timestamp":1695815021000},"page":"591-600","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Most DNA repair defects do not modify the relationship between relative biological effectiveness and linear energy transfer in CRISPR\u2010edited cells"],"prefix":"10.1002","volume":"51","author":[{"given":"Francisco D. C.","family":"Guerra Liberal","sequence":"first","affiliation":[{"name":"The Patrick G Johnston Centre for Cancer Research Queen's University Belfast  Belfast UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason L.","family":"Parsons","sequence":"additional","affiliation":[{"name":"Institute of Cancer and Genomic Sciences University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"McMahon","sequence":"additional","affiliation":[{"name":"The Patrick G Johnston Centre for Cancer Research Queen's University Belfast  Belfast UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,27]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1993.434"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1088\/0031\u20109155\/38\/6\/001"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.14338\/IJPT\u201020\u201000089.1"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11070946"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24054920"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/09553009314450721"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1667\/RR3171"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1667\/RR3489.1"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2011.06.019"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/ANNUREV.BIOCHEM.052308.093131"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.DNAREP.2005.03.005"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.16.5706"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.DNAREP.2008.01.010"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2014.12.046"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2015.08.014"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2013.09.041"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1667\/RR13904.1"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9040889"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1667\/RR13904.1.The"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/mp.14878"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1667\/RR13782.1"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0360-3016(00)00568-X"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1667\/RADE\u201022\u201000040.1"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2017.30"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.18"},{"key":"e_1_2_11_27_1","first-page":"7861","article-title":"Characterization of intrinsic radiation sensitivity in a diverse panel of normal, cancerous and CRISPR\u2010modified cell lines","volume":"24","author":"Guerra Liberal FDC","year":"2023","journal-title":"Int J Med Sci"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apradiso.2021.109931"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apradiso.2008.06.012"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2019.02.053"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2017.11.012"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2015.07.2279"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmp.2012.10.001"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.103.5.653"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.7150\/THNO.15019"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2016.01.046"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/mp.15850"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2018.12.028"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2019.08.011"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001622\u2010199511000\u201000013"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2009.276"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.27"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz1167"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.MOLCEL.2004.10.029"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2005.02.001"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03585-5"}],"container-title":["Medical Physics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/aapm.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mp.16764","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T20:55:29Z","timestamp":1705611329000},"score":1,"resource":{"primary":{"URL":"https:\/\/aapm.onlinelibrary.wiley.com\/doi\/10.1002\/mp.16764"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,27]]},"references-count":45,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1]]}},"alternative-id":["10.1002\/mp.16764"],"URL":"https:\/\/doi.org\/10.1002\/mp.16764","archive":["Portico"],"relation":{},"ISSN":["0094-2405","2473-4209"],"issn-type":[{"value":"0094-2405","type":"print"},{"value":"2473-4209","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,27]]},"assertion":[{"value":"2023-06-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}