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 Gorbunova; Alan Meeker; Chris Jones; Pedro R. Lowenstein; Maria G. Castro

doi:10.1126/scitranslmed.aac8228

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 Meeker, Chris Jones, Pedro R. Lowenstein, Maria G. Castro

School of Medicine

Research output: Contribution to journal › Article › peer-review

117 Scopus citations

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 language	English (US)
Article number	328ra28
Journal	Science translational medicine
Volume	8
Issue number	328
DOIs	https://doi.org/10.1126/scitranslmed.aac8228
State	Published - Mar 2 2016

ASJC Scopus subject areas

General Medicine

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Koschmann, C., Calinescu, A. A., Nunez, F. J., Mackay, A., Fazal-Salom, J., Thomas, D., Mendez, F., Kamran, N., Dzaman, M., Mulpuri, L., Krasinkiewicz, J., Doherty, R., Lemons, R., Brosnan-Cashman, J. A., Li, Y., Roh, S., Zhao, L., Appelman, H., Ferguson, D., ... Castro, M. G. (2016). ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Science translational medicine, 8(328), Article 328ra28. https://doi.org/10.1126/scitranslmed.aac8228

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, A, 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

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title = "ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma",

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.",

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

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AU - Koschmann, Carl

AU - Calinescu, Anda Alexandra

AU - Nunez, Felipe J.

AU - Mackay, Alan

AU - Fazal-Salom, Janet

AU - Thomas, Daniel

AU - Mendez, Flor

AU - Kamran, Neha

AU - Dzaman, Marta

AU - Mulpuri, Lakshman

AU - Krasinkiewicz, Johnathon

AU - Doherty, Robert

AU - Lemons, Rosemary

AU - Brosnan-Cashman, Jaqueline A.

AU - Li, Youping

AU - Roh, Soyeon

AU - Zhao, Lili

AU - Appelman, Henry

AU - Ferguson, David

AU - Gorbunova, Vera

AU - Meeker, Alan

AU - Jones, Chris

AU - Lowenstein, Pedro R.

AU - Castro, Maria G.

PY - 2016/3/2

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N2 - 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.

AB - 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.

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

Abstract

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