Abstract
Huntington's disease (HD) is an autosomal-dominant neurological disorder caused by expanded CAG repeats in the Huntingtin (Htt) gene, but it is not known how this mutation causes neurodegeneration. Herein, we found that dysfunction of upstream binding factor-1 (UBF-1) is linked to reduced ribosomal DNA (rDNA) transcription in HD. We identified that UBF1 acetylation at Lys (K) 352 by CREB binding protein (CBP) is crucial for the transcriptional activity of rDNA. UBF1 mutation (K352A, K352Q, and K352R) decreased rDNA transcriptional activity. Moreover, both CBP–dHAT mutant and knockdown of CBP by siRNA reduced acetylation of UBF1 and resulted in the decreased transcription of rDNA into rRNA. ChIP analysis showed a significant reduction of UBF1 occupancy in the promoter of rDNA in STHdhQ111 cell line model of HD. These results demonstrate that abnormal activity of UBF1 and its acetylation by CBP are linked to impaired rDNA transcription in HD. This novel mechanism suggests that modulation of UBF-mediated rDNA synthesis by CBP may be a therapeutic target for improving neuronal rDNA transcription in HD.
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Accession codes
Abbreviations
- ENH:
-
enhancer
- UCE:
-
upstream control element
- CORE:
-
core region
- ETS:
-
external transcribed spacer
- 5-FU:
-
5-fluorouracil
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Acknowledgements
We thank Dr. Samson T. Jacob for pIRES-Luc and Human rRNA-luciferase Vector and Dr. Marcy MacDonald for STHdhQ7/7 and STHdhQ111/111 cells. We thank Dr. Byoung Yul Soh for his technical assistance. This study was supported by WCU Neurocytomics Program Grant (800-20080848) (H.R.) and SRC Grant (2010-0029-403) (H.R.) from KOSEF and NIH NS52724 (H.R.). This work was also supported in part by the Converging Research Center Program (20090094081) (Y.K.) through NRF of Korea.
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Lee, J., Hwang, Y., Boo, J. et al. Dysregulation of upstream binding factor-1 acetylation at K352 is linked to impaired ribosomal DNA transcription in Huntington's disease. Cell Death Differ 18, 1726–1735 (2011). https://doi.org/10.1038/cdd.2011.38
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DOI: https://doi.org/10.1038/cdd.2011.38
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