Expansion of tandem repeat sequences is responsible for more than 20 human 
diseases. Several cis elements and trans factors involved in repeat instability 
(expansion and contraction) have been identified. However no comprehensive model 
explaining large intergenerational or somatic changes of the length of the 
repeating sequences exists. Several lines of evidence, accumulated from 
different model studies, indicate that transcription through repeat sequences is 
an important factor promoting their instability. The persistent interaction 
between transcription template DNA and nascent RNA (RNA•DNA hybrids, R loops) 
was shown to stimulate genomic instability. Recently, we demonstrated that 
cotranscriptional RNA•DNA hybrids are preferentially formed at GC-rich 
trinucleotide and tetranucleotide repeat sequences in vitro as well as in human 
genomic DNA. Additionally, we showed that cotranscriptional formation of RNA•DNA 
hybrids at CTG•CAG and GAA•TTC repeats stimulate instability of these sequences 
in both E. coli and human cells. Our results suggest that persistent RNA•DNA 
hybrids may also be responsible for other downstream effects of expanded 
trinucleotide repeats, including gene silencing. Considering the extent of 
transcription through the human genome as well as the abundance of GC-rich 
and/or non-canonical DNA structure forming tandem repeats, RNA•DNA hybrids may 
represent a common mutagenic conformation. Hence, R loops are potentially 
attractive therapeutic target in diseases associated with genomic instability.