ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma

Carl Koschmann, Anda Alexandra Calinescu, Felipe J. Nunez, Alan Mackay, Janet Fazal-Salom, Daniel Thomas, Flor Mendez, Neha Kamran, Marta Dzaman, Lakshman Mulpuri, Johnathon Krasinkiewicz, Robert Doherty, Rosemary Lemons, Jaqueline A. Brosnan-Cashman, Youping Li, Soyeon Roh, Lili Zhao, Henry Appelman, David Ferguson, Vera GorbunovaAlan Keith Meeker, Chris Jones, Pedro R. Lowenstein, Maria G. Castro

Research output: Contribution to journalArticle

Abstract

Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and showed that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single-nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs nonhomologous end joining and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival.

Original languageEnglish (US)
Article number328ra28
JournalScience Translational Medicine
Volume8
Issue number328
DOIs
StatePublished - Mar 2 2016

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DNA End-Joining Repair
Glioblastoma
Glioma
Histone Chaperones
Mutation
Survival
Double-Stranded DNA Breaks
DNA
Mutation Rate
Growth
Neoplasms
Nucleotides
Animal Models
Genome
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Koschmann, C., Calinescu, A. A., Nunez, F. J., Mackay, A., Fazal-Salom, J., Thomas, D., ... Castro, M. G. (2016). ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Science Translational Medicine, 8(328), [328ra28]. https://doi.org/10.1126/scitranslmed.aac8228

ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. / Koschmann, Carl; Calinescu, Anda Alexandra; Nunez, Felipe J.; Mackay, Alan; Fazal-Salom, Janet; Thomas, Daniel; Mendez, Flor; Kamran, Neha; Dzaman, Marta; Mulpuri, Lakshman; Krasinkiewicz, Johnathon; Doherty, Robert; Lemons, Rosemary; Brosnan-Cashman, Jaqueline A.; Li, Youping; Roh, Soyeon; Zhao, Lili; Appelman, Henry; Ferguson, David; Gorbunova, Vera; Meeker, Alan Keith; Jones, Chris; Lowenstein, Pedro R.; Castro, Maria G.

In: Science Translational Medicine, Vol. 8, No. 328, 328ra28, 02.03.2016.

Research output: Contribution to journalArticle

Koschmann, C, Calinescu, AA, Nunez, FJ, Mackay, A, Fazal-Salom, J, Thomas, D, Mendez, F, Kamran, N, Dzaman, M, Mulpuri, L, Krasinkiewicz, J, Doherty, R, Lemons, R, Brosnan-Cashman, JA, Li, Y, Roh, S, Zhao, L, Appelman, H, Ferguson, D, Gorbunova, V, Meeker, AK, Jones, C, Lowenstein, PR & Castro, MG 2016, 'ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma', Science Translational Medicine, vol. 8, no. 328, 328ra28. https://doi.org/10.1126/scitranslmed.aac8228
Koschmann C, Calinescu AA, Nunez FJ, Mackay A, Fazal-Salom J, Thomas D et al. ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Science Translational Medicine. 2016 Mar 2;8(328). 328ra28. https://doi.org/10.1126/scitranslmed.aac8228
Koschmann, Carl ; Calinescu, Anda Alexandra ; Nunez, Felipe J. ; Mackay, Alan ; Fazal-Salom, Janet ; Thomas, Daniel ; Mendez, Flor ; Kamran, Neha ; Dzaman, Marta ; Mulpuri, Lakshman ; Krasinkiewicz, Johnathon ; Doherty, Robert ; Lemons, Rosemary ; Brosnan-Cashman, Jaqueline A. ; Li, Youping ; Roh, Soyeon ; Zhao, Lili ; Appelman, Henry ; Ferguson, David ; Gorbunova, Vera ; Meeker, Alan Keith ; Jones, Chris ; Lowenstein, Pedro R. ; Castro, Maria G. / ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. In: Science Translational Medicine. 2016 ; Vol. 8, No. 328.
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