title: RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells.
abstract: Patients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs.
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Harry O
authors.initials: HO
authors.lastname: King
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Brend
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Payne
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wright
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Ward
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Karan
authors.initials: K
authors.lastname: Patel
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Teklu
authors.initials: T
authors.lastname: Egnuni
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Lucy F
authors.initials: LF
authors.lastname: Stead
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Anjana
authors.initials: A
authors.lastname: Patel
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Heiko
authors.initials: H
authors.lastname: Wurdak
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK. Electronic address: s.c.short@leeds.ac.uk.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Short
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects*; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D011838:Radiation-Sensitizing Agents; D055748:SOXB1 Transcription Factors; D051135:Rad51 Recombinase
keywords: RAD51; glioblastoma; glioma stem cell; radiosensitization