Nucleic Acids Research Advance Access originally published online on November 27, 2007
Nucleic Acids Research 2008 36(2):489-500; doi:10.1093/nar/gkm1066
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Nucleic Acids Research, 2008, Vol. 36, No. 2 489-500
© 2007 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 |
Repair of DNA double-strand breaks within the (GAA•TTC)n sequence results in frequent deletion of the triplet-repeat sequence
1Department of Biochemistry and Molecular Biology and 2Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
*To whom correspondence should be addressed. Tel: +(405) 271 1360; Fax: +(405) 271 3910; Email: Sanjay-Bidichandani{at}ouhsc.edu
Received August 9, 2007. Revised November 7, 2007. Accepted November 12, 2007.
Friedreich ataxia is caused by an expanded (GAA•TTC)n sequence, which is unstable during intergenerational transmission and in most patient tissues, where it frequently undergoes large deletions. We investigated the effect of DSB repair on instability of the (GAA•TTC)n sequence. Linear plasmids were transformed into Escherichia coli so that each colony represented an individual DSB repair event. Repair of a DSB within the repeat resulted in a dramatic increase in deletions compared with circular templates, but DSB repair outside the repeat tract did not affect instability. Repair-mediated deletions were independent of the orientation and length of the repeat, the location of the break within the repeat or the RecA status of the strain. Repair at the center of the repeat resulted in deletion of approximately half of the repeat tract, and repair at an off-center location produced deletions that were equivalent in length to the shorter of the two repeats flanking the DSB. This is consistent with a single-strand annealing mechanism of DSB repair, and implicates erroneous DSB repair as a mechanism for genetic instability of the (GAA•TTC)n sequence. Our data contrast significantly with DSB repair within (CTG•CAG)n repeats, indicating that repair-mediated instability is dependent on the sequence of the triplet repeat.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. Soragni, D. Herman, S. Y. R. Dent, J. M. Gottesfeld, R. D. Wells, and M. Napierala Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia Nucleic Acids Res., November 1, 2008; 36(19): 6056 - 6065. [Abstract] [Full Text] [PDF]
|
|