Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 360, Issue 1, Pages 21-36Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2006.05.012
Keywords
tetranucleotide repeats; recombination; expansions; DNA thermodynamic; stabilities; SOS repair
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Funding
- NIEHS NIH HHS [ES11347] Funding Source: Medline
- NINDS NIH HHS [NS37554] Funding Source: Medline
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Myotonic dystrophy type 2 (DM2) is caused by the extreme expansion of the repeating tetranucleotide CCTG center dot CAGG sequence from < 30 repeats in normal individuals to similar to 11,000 for the full mutation in certain patients. This repeat is in intron I of the zinc finger protein 9 gene on chromosome 3q21. Since prior work demonstrated that CTG center dot CAG and GAA center dot TTC triplet repeats (responsible for DM1 and Friedreich's ataxia, respectively) can expand by genetic recombination, we investigated the capacity of the DM2 tetranucleotide repeats to also expand during this process. Both gene conversion and unequal crossing over are attractive mechanisms to effect these very large expansions. (CCTG *CAGG)(n) (where n = 30, 75, 114 or 160) repeats showed high recombination crossover frequencies (up to 27-fold higher than the non-repeating control) in an intramolecular plasmid system in Escherichia coli. Furthermore, a distinct orientation effect was observed where orientation 11 (CAGG on the leading strand template) was more prone to recombine. Expansions of up to double the length of the tetranucleotide repeats were found. Also, the repeating tetra nucleotide sequence was more prone to expansions (to give lengths longer than a single repeating tract) than deletions as observed for the CTG center dot CAG and GAA center dot TTC repeats. We determined that the DM2 tetranucleotide repeats showed a lower thermodynamic stability when compared to the DM1 trinucleotide repeats, which could make them better targets for DNA repair events, thus explaining their expansion-prone behavior. Genetic studies in SOS-repair mutants revealed high frequencies of recombination crossovers although the SOS-response itself was not induced. Thus, the genetic instabilities of the CCTG center dot CAGG repeats may be mediated by a recombination-repair mechanism that is influenced by DNA structure. (c) 2006 Elsevier Ltd. All rights reserved.
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