Expandable DNA repeats and human disease

  title={Expandable DNA repeats and human disease},
  author={Sergei M. Mirkin},
Nearly 30 hereditary disorders in humans result from an increase in the number of copies of simple repeats in genomic DNA. These DNA repeats seem to be predisposed to such expansion because they have unusual structural features, which disrupt the cellular replication, repair and recombination machineries. The presence of expanded DNA repeats alters gene expression in human cells, leading to disease. Surprisingly, many of these debilitating diseases are caused by repeat expansions in the non… 

Instability of the DNA repeats mutation in humans hereditary disorders

The unusual DNA structures, molecular mechanisms of repeat expansions and modes of disease pathogenesis in the processes of DNA repeats instability are reviewed and compared.

Features of trinucleotide repeat instability in vivo

Most in vivo data are consistent with a model in which expansion and deletion occur by different mechanisms, and in mammals, microsatellite instability is complex and appears to be influenced by genetic, epigenetic and developmental factors.

The balancing act of DNA repeat expansions.

Trinucleotide repeats: triggers for genomic disorders?

In conclusion, long TGG repeat tracts were shown to be implicated in a genomic disorder resulting from chromosome 14q32.2 deletion, and looking at the problem from a structural biology perspective may help.

DNA Structures In Vivo and Repeat Instability

The aim of this review is to give a general overview of unstable repeats diseases, highlight the complexities of these diseases, and feature the emerging discoveries in the field.

Mystery of Expansion: DNA Metabolism and Unstable Repeats.

The mammalian genome mostly contains repeated sequences, and their instability, particularly the propensity to change the repeat unit number, is responsible for 36 well-known neurodegenerative human disorders.

Small Molecule Modulates Hairpin Structures in CAG Trinucleotide Repeats

It is demonstrated that NA can induce hairpin secondary structures on d(CAG)n repeats, which then efficiently interfere with DNA replication by Taq DNA polymerase.

Trinucleotide repeat expansions catalyzed by human cell-free extracts

A novel in vitro assay is used to show that human cell-free extracts catalyze expansions and contractions of trinucleotide repeats without the requirement for DNA replication, suggesting that this important mutagenic process can be restored in the test tube.



DNA structures, repeat expansions and human hereditary disorders.

  • S. Mirkin
  • Biology
    Current opinion in structural biology
  • 2006

Expansion and deletion of CTG repeats from human disease genes are determined by the direction of replication in E. coli

It is shown that the frequency of genetic expansions or deletions in Escherichia coli depends on the direction of replication, which relates to expansion–deletion mechanisms in eukaryotic chromosomes for disease genes.

Expansion and length-dependent fragility of CTG repeats in yeast.

The genetic assay described here can be used to evaluate other factors that induce TNR expansion or chromosome fragility in humans and is suitable to evaluate length-dependent destabilization of CTG tracts.

Repeat instability: mechanisms of dynamic mutations

Experimental advances towards explaining the mechanisms of repeat instability have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.

DNA secondary structure: a common and causative factor for expansion in human disease.

  • C. McMurray
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
Although different genes are affected and different features of pathogenesis are evident, there is a common pattern of unstable transmission among the trinucleotide repeat diseases, suggesting common elements to the mechanism.

Replication fork regression in repetitive DNAs

Among several different types of repetitive sequences found in the human genome, this study has examined the telomeric repeat, necessary for the protection of chromosome termini, and the

Alternative structures in duplex DNA formed within the trinucleotide repeats of the myotonic dystrophy and fragile X loci.

The formation of novel alternative DNA secondary structures that map within the repeat tracts during reannealing of complementary strands, containing equal lengths of repeats, into linear duplex DNA molecules are reported.

CGG repeats associated with DNA instability and chromosome fragility form structures that block DNA synthesis in vitro.

It is shown here that CGG repeats readily form a series of barriers to DNA synthesis in vitro, which are K(+)-dependent, template concentration-independent, and involve hydrogen bonding between guanines.

Triplet repeats form secondary structures that escape DNA repair in yeast.

It is shown that single-stranded DNA loops containing 10 CTG/CAG or CGG/CCG repeats are inefficiently repaired during meiotic recombination in Saccharomyces cerevisiae and comparisons of the repair of DNA loops with palindromic and nonpalindromed sequences suggest that this inefficient repair reflects the ability of these sequences to form hairpin structures in vivo.

Long CTG Tracts from the Myotonic Dystrophy Gene Induce Deletions and Rearrangements during Recombination at the APRT Locus in CHO Cells

These studies indicate that homologous recombination strongly destabilizes long tracts of CTG repeats, which are thought to arise from their capacity to form hairpin DNA structures.