Nucleic Acids Research Advance Access originally published online on October 11, 2007
Nucleic Acids Research 2007 35(20):6884-6894; doi:10.1093/nar/gkm810
Nucleic Acids Research, 2007, Vol. 35, No. 20 6884-6894
© 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 |
Deficiency of RecA-dependent RecFOR and RecBCD pathways causes increased instability of the (GAA·TTC)n sequence when GAA is the lagging strand template
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 June 29, 2007. Revised September 17, 2007. Accepted September 18, 2007.
The most common mutation in Friedreich ataxia is an expanded (GAA·TTC)n sequence, which is highly unstable in human somatic cells and in the germline. The mechanisms responsible for this genetic instability are poorly understood. We previously showed that cloned (GAA·TTC)n sequences replicated in Escherichia coli are more unstable when GAA is the lagging strand template, suggesting erroneous lagging strand synthesis as the likely mechanism for the genetic instability. Here we show that the increase in genetic instability when GAA serves as the lagging strand template is seen in RecA-deficient but not RecA-proficient strains. We also found the same orientation-dependent increase in instability in a RecA+ temperature-sensitive E. coli SSB mutant strain (ssb-1). Since stalling of replication is known to occur within the (GAA·TTC)n sequence when GAA is the lagging strand template, we hypothesized that genetic stability of the (GAA·TTC)n sequence may require efficient RecA-dependent recombinational restart of stalled replication forks. Consistent with this hypothesis, we noted significantly increased instability when GAA was the lagging strand template in strains that were deficient in components of the RecFOR and RecBCD pathways. Our data implicate defective processing of stalled replication forks as a mechanism for genetic instability of the (GAA·TTC)n sequence.
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