Breakpoints of Gross Deletions Coincide with Non-B DNA Conformations

Genomic rearrangements are a frequent source of instability, but the mechanisms involved are poorly understood. A 2.5-kbp poly(purine·pyrimidine) sequence from the human PKD1 gene, known to form non-B DNA structures, induced long deletions and other instabilities in plasmids that were mediated by mi...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 101; no. 39; pp. 14162 - 14167
Main Authors Bacolla, Albino, Jaworski, Adam, Larson, Jacquelynn E., Jakupciak, John P., Chuzhanova, Nadia, Abeysinghe, Shaun S., O'Connell, Catherine D., Cooper, David N., Wells, Robert D., Modrich, Paul L.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 28.09.2004
National Acad Sciences
Subjects
Base Composition
Base Sequence
Biological Sciences
Chromosome Breakage - genetics
Colony Count, Microbial
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA - genetics
DNA mismatch repair
DNA Repair
Escherichia coli - genetics
Escherichia coli - growth & development
Fluorescence
Gene Deletion
Gene Rearrangement
Genes
Genetic mutation
Genetics
Genomics
Humans
Introns
Isopropyl Thiogalactoside - pharmacology
Molecular Sequence Data
Nucleic Acid Conformation
Nucleotide sequences
Nucleotides
Plasmids
Plasmids - genetics
Polycystic Kidney, Autosomal Dominant - genetics
Restriction Mapping - methods
Transcription, Genetic - drug effects
Transformation, Bacterial
Translocation, Genetic - genetics
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Summary:Genomic rearrangements are a frequent source of instability, but the mechanisms involved are poorly understood. A 2.5-kbp poly(purine·pyrimidine) sequence from the human PKD1 gene, known to form non-B DNA structures, induced long deletions and other instabilities in plasmids that were mediated by mismatch repair and, in some cases, transcription. The breakpoints occurred at predicted non-B DNA structures. Distance measurements also indicated a significant proximity of alternating purine-pyrimidine and oligo(purine·pyrimidine) tracts to breakpoint junctions in 222 gross deletions and translocations, respectively, involved in human diseases. In 11 deletions analyzed, breakpoints were explicable by non-B DNA structure formation. We conclude that alternative DNA conformations trigger genomic rearrangements through recombination-repair activities.
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To whom correspondence should be addressed. E-mail: rwells@ibt.tamushsc.edu.
Abbreviations: IPTG, isopropyl β-d-thiogalactoside; wt, wild-type; CFUs, colony-forming units.
Communicated by Paul L. Modrich, Duke University Medical Center, Durham, NC, August 13, 2004
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0405974101