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 | |
| State | Published - Mar 2 2016 |
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ASJC Scopus subject areas
- Medicine(all)
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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 journal › Article
}
TY - JOUR
T1 - ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma
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 Keith
AU - Jones, Chris
AU - Lowenstein, Pedro R.
AU - Castro, Maria G.
PY - 2016/3/2
Y1 - 2016/3/2
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.
UR - http://www.scopus.com/inward/record.url?scp=84959523012&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84959523012&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aac8228
DO - 10.1126/scitranslmed.aac8228
M3 - Article
C2 - 26936505
AN - SCOPUS:84959523012
VL - 8
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 328
M1 - 328ra28
ER -