Nucleic Acids Research Advance Access originally published online on August 31, 2006
Nucleic Acids Research 2006 34(16):4495-4505; doi:10.1093/nar/gkl614
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Nucleic Acids Research, 2006, Vol. 34, No. 16 4495-4505
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
CAG·CTG repeat instability in cultured human astrocytes
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center Box 986805, Omaha, NE 68198-6805, USA 1 Department of Pathology and Microbiology, University of Nebraska Medical Center Box 986805, Omaha, NE 68198-6805, USA
*To whom correspondence should be addressed. Tel: +1 402 559 4619; Fax: +1 402 559 8270; Email: rlahue{at}unmc.edu
Received July 11, 2006. Revised August 3, 2006. Accepted August 6, 2006.
Cells of the central nervous system (CNS) are prone to the devastating consequences of trinucleotide repeat (TNR) expansion. Some CNS cells, including astrocytes, show substantial TNR instability in affected individuals. Since astrocyte enrichment occurs in brain regions sensitive to neurodegeneration and somatic TNR instability, immortalized SVG-A astrocytes were used as an ex vivo model to mimic TNR mutagenesis. Cultured astrocytes produced frequent (up to 2%) CAG·CTG contractions in a sequence-specific fashion, and an apparent threshold for instability was observed between 25 and 33 repeats. These results suggest that cultured astrocytes recapitulate key features of TNR mutagenesis. Furthermore, contractions were influenced by DNA replication through the repeat, suggesting that instability can arise by replication-based mechanisms in these cells. This is a crucial mechanistic point, since astrocytes in the CNS retain proliferative capacity throughout life and could be vulnerable to replication-mediated TNR instability. The presence of interruptions led to smaller but more frequent contractions, compared to a pure repeat, and the interruptions were sometimes deleted to form a perfect tract. In summary, we suggest that CAG·CTG repeat instability in cultured astrocytes is dynamic and replication-driven, suggesting that TNR mutagenesis may be influenced by the proliferative capacity of key CNS cells.
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  D. A. Claassen and R. S. Lahue Expansions of CAG{middle dot}CTG repeats in immortalized human astrocytes Hum. Mol. Genet., December 15, 2007; 16(24): 3088 - 3096. [Abstract] [Full Text] [PDF]
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