Effects of Friedreich's ataxia (GAA)n*(TTC)n repeats on RNA synthesis and stability.

Abstract:

:Expansions of (GAA)n repeats within the first intron of the frataxin gene reduce its expression, resulting in a hereditary neurodegenerative disorder, Friedreich's ataxia. While it is generally believed that expanded (GAA)n repeats block transcription elongation, fine mechanisms responsible for gene repression are not fully understood. To follow the effects of (GAA)n*(TTC)n repeats on gene expression, we have chosen E. coli as a convenient model system. (GAA)n*(TTC)n repeats were cloned into bacterial plasmids in both orientations relative to a promoter, and their effects on transcription and RNA stability were evaluated both in vitro and in vivo. Expanded (GAA)n repeats in the sense strand for transcription caused a significant decrease in the mRNA levels in vitro and in vivo. This decrease was likely due to the tardiness of the RNA polymerase within expanded (GAA)n runs but was not accompanied by the enzyme's dissociation and premature transcription termination. Unexpectedly, positioning of normal- and carrier-size (TTC)n repeats into the sense strand for transcription led to the appearance of RNA transcripts that were truncated within those repetitive runs in vivo. We have determined that these RNA truncations are consistent with cleavage of the full-sized mRNAs at (UUC)n runs by the E. coli degradosome.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Krasilnikova MM,Kireeva ML,Petrovic V,Knijnikova N,Kashlev M,Mirkin SM

doi

10.1093/nar/gkl1140

subject

Has Abstract

pub_date

2007-01-01 00:00:00

pages

1075-84

issue

4

eissn

0305-1048

issn

1362-4962

pii

gkl1140

journal_volume

35

pub_type

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