Autonomous expansions of trinucleotide repeats with the general structure 5`-d(CNG)-3` are associated with several human genetic diseases. We have characterized nuclear proteins binding to the unstable 5`-d(CGG)-3` repeat. Its expansion in the human FMR1 gene leads to the fragile X syndrome, one of the most frequent causes of mental retardation in human males. Electrophoretic mobility shift assays using nuclear extracts from several human and other mammalian cell lines and from primary human cells demonstrated specific binding to double-stranded DNA fragments containing only a 5`-d(CGG)-3` repeat or the repeat and flanking genomic sequences of the human FMR1 gene. Protein binding was inhibited by complete methylation of the trinucleotide repeat. The complex formed with crude nuclear extract apparently did not contain the human transcription factor Sp1 that binds to a characteristic GC-rich sequence. A 20-kDa protein involved in specific binding to the double-stranded 5`-d(CGG)-3` repeat was purified from HeLa nuclear extracts by DNA affinity chromatography.

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