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Musashi1 Impacts Radio-Resistance in Glioblastoma by Controlling DNA-Protein Kinase Catalytic Subunit

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The conserved RNA-binding protein Musashi1 (MSI1) has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation and as a key oncogenic factor in numerous solid tumors, including glioblastoma. To explore the potential use of MSI1 targeting in therapy, we studied MSI1 in the context of radiation sensitivity. Knockdown of MSI1 led to a decrease in cell survival and an increase in DNA damage compared to control in cells treated with ionizing radiation. We subsequently examined mechanisms of double-strand break repair and found that loss of MSI1 reduces the frequency of nonhomologous end-joining. This phenomenon could be attributed to the decreased expression of DNA–protein kinase catalytic subunit, which we have previously identified as a target of MSI1. Collectively, our results suggest a role for MSI1 in double-strand break repair and that its inhibition may enhance the effect of radiotherapy.

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Supported by Cancer Prevention Research Institute of Texas (CPRIT) fellowship RP140105 (P.R.d.A.), CPRIT Greehey fellowship RP101491 (A.G.), a Translational Science Training Across Disciplines Scholarship from the University of Texas System Graduate Programs Initiative (A.G.), National Cancer Institute T32 postdoctoral training fellowship T32CA148724 (A.G.) and training grant 5T32CA148724-2 (S.S.T.), a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil (A.E.d.S.). Work performed in the Bishop laboratory was supported by NIH grants K22ES012264, 1R15ES019128, and 1R01CA152063. Work performed in the Penalva laboratory was supported by The Max and Minnie Tomerlin Voelcker Fund grants 1R01HG006015-01A and 1R21CA175875-01A1, The Institute for Integration of Medicine and Sciences (IIMS)-Cancer Therapy & Research Center (CTRC) (University of Texas Health Sciences Center at San Antonio), and Voices Against Brain Cancer (VABC; L.O.F.P.).

Disclosures: None declared.

P.R.d.A., A.G., and A.E.d.S. contributed equally to this work.

Current address of D.T.V., Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.