Small slipped register genetic instabilities in Escherichia coli in triplet repeat sequences associated with hereditary neurological diseases.
Genetic instability investigations on three triplet repeat sequences (TRS) involved in human hereditary neurological diseases (CTG.CAG, CGG.CCG, and GAA.TTC) revealed a high frequency of small expansions or deletions in 3-base pair registers in Escherichia coli. The presence of G to A polymorphisms in the CTG.CAG sequences served as reporters for the size and location of these instabilities. For the other two repeat sequences, length determinations confirmed the conclusions found for CTG.CAG. These studies were conducted in strains deficient in methyl-directed mismatch repair or nucleotide excision repair in order to investigate the involvement of these postreplicative processes in the genetic instabilities of these TRS. The observation that small and large instabilities for (CTG.CAG)175 fall into distinct size classes (1-8 repeats and approximate multiples of 41 repeats, respectively) leads to the conclusion that more than one DNA instability process is involved. The slippage of the complementary strands of the TRS is probably responsible for the small deletions and expansions in methyl-directed mismatch repair-deficient and nucleotide excision repair-deficient cells. A model is proposed to explain the observed instabilities via strand misalignment, incision, or excision, followed by DNA synthesis and ligation. This slippage-repair mechanism may be responsible for the small expansions in type 1 hereditary neurological diseases involving polyglutamine expansions. Furthermore, these observations may relate to the high frequency of small deletions versus a lower frequency of large instabilities observed in lymphoblastoid cells from myotonic dystrophy patients.
Institute of Biosciences and Technology, Center for Genome Research, Department of Biochemistry and Biophysics, Texas A & M University, Texas Medical Center, Houston, Texas 77030-3303, USA. rwells@ibt.tamu.edu
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Wells
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Parniewski
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Pluciennik
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Bacolla
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Gellibolian
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Jaworski
D004260:DNA Repair / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D009223:Myotonic Dystrophy / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics*; D010455:Peptides / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D018911:Trinucleotide Repeats / Q000235:genetics*
D010455:Peptides; C097188:polyglutamine