MartinPNAS10238002005 - Microsatellite instability...

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Unformatted text preview: Microsatellite instability regulates transcription factor binding and gene expression Patricia Martin* † , Katherine Makepeace*, Stuart A. Hill ‡ , Derek W. Hood*, and E. Richard Moxon* *Molecular Infectious Diseases Group, University of Oxford Department of Paediatrics, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; and ‡ Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115 Edited by John R. Roth, University of California, Davis, CA, and approved January 21, 2005 (received for review September 14, 2004) Microsatellites are tandemly repeated simple sequence DNA motifs widely prevalent in eukaryotic and prokaryotic genomes. In patho- genic bacteria, instability of these hypermutable loci through slipped-strand mispairing mediates the high-frequency reversible switching of phenotype expression, i.e., phase variation. Phase- variable expression of NadA, an outer membrane protein and adhesin of the pathogen Neisseria meningitidis , is mediated by changes in the number of TAAA repeats located upstream of the core promoter of nadA . Here we report that loss or gain of TAAA repeats affects the binding of the transcriptional regula- tory protein IHF to the nadA promoter. Thus, phase-variable transcription of nadA potentially incorporates interplay between stochastic (mutational) and prescriptive (classical) mechanisms of gene regulation. phase variation N eisseria meningitidis is a Gram-negative encapsulated bac- terium predominantly found in the human nasopharynx, where it can be a constituent of the normal microbial flora. However, some strains are invasive and penetrate first the blood and then the meninges to cause septicemia and menin- gitis. N. meningitidis has evolved several environmentally induced regulatory systems to control the expression of the virulence factors that are differentially expressed during the establishment of the infection (1–3). Phase variation, which results in high-frequency switching of phenotype expression, relies on environment-independent stochastic changes occur- ring within repeated simple sequence DNA motifs located in coding or promoter regions of numerous genes potentially involved in pathogenicity (4). Addition or subtraction of repeated units creates frameshifts and premature stop codons (5) or alters the strength of the promoter (6–8). The nadA gene, which encodes an outer membrane protein and adhesin (9), was recently shown to be present in 50% of the disease-associated N. meningitidis strains and in 100% of the strains belonging to hypervirulent lineages ET-5, ET-37, and cluster A4, but in only 16% of the strains isolated from healthy people (10). NadA is currently under investigation as a vaccine candidate (11). The phase-variable expression of the nadA gene was recently shown to be regulated at the transcriptional level through a variation of the number of reiterated TAAA motifs present in the repeat tract located upstream of the core promoter...
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MartinPNAS10238002005 - Microsatellite instability...

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