Skip to main content
Article thumbnail
Location of Repository

Effects of Friedreich's ataxia GAA repeats on DNA replication in mammalian cells

By Gurangad S. Chandok, Mayank P. Patel, Sergei M. Mirkin and Maria M. Krasilnikova


Friedreich's ataxia (FRDA) is a common hereditary degenerative neuro-muscular disorder caused by expansions of the (GAA)n repeat in the first intron of the frataxin gene. The expanded repeats from parents frequently undergo further significant length changes as they are passed on to progeny. Expanded repeats also show an age-dependent instability in somatic cells, albeit on a smaller scale than during intergenerational transmissions. Here we studied the effects of (GAA)n repeats of varying lengths and orientations on the episomal DNA replication in mammalian cells. We have recently shown that the very first round of the transfected DNA replication occurs in the lack of the mature chromatin, does not depend on the episomal replication origin and initiates at multiple single-stranded regions of plasmid DNA. We now found that expanded GAA repeats severely block this first replication round post plasmid transfection, while the subsequent replication cycles are only mildly affected. The fact that GAA repeats affect various replication modes in a different way might shed light on their differential expansions characteristic for FRDA

Topics: Genome Integrity, Repair and Replication
Publisher: Oxford University Press
OAI identifier:
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles


    1. (2011). A distinct first replication cycle of DNA introduced in mammalian cells.
    2. (2000). Bi-directional replication and random termination.
    3. (2008). Chromosome fragility at GAA tracts in yeast depends on repeat orientation and requires mismatch repair.
    4. (1996). Clinical and genetic abnormalities in patients with Friedreich’s ataxia.
    5. (2009). Development of histone deacetylase inhibitors as therapeutics for neurological disease.
    6. (2003). DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing.
    7. (2008). DNA triplexes and Friedreich ataxia.
    8. (2007). Effects of Friedreich’s ataxia (GAA)n*(TTC)n repeats on RNA synthesis and stability.
    9. (1997). Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes.
    10. (2010). Friedreich’s ataxia induced pluripotent stem cells model intergenerational GAATTC triplet repeat instability.
    11. (1996). Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.
    12. (1998). GAA instability in Friedreich’s ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases.
    13. (2010). Getting to the core of repeat expansions by cell reprogramming.
    14. (2003). Hairpin formation in Friedreich’s ataxia triplet repeat expansion.
    15. (2009). Large-scale expansions of Friedreich’s ataxia GAA repeats in yeast.
    16. (2004). Length-dependent structure formation in Friedreich ataxia (GAA)n*(TTC)n repeats at neutral pH.
    17. (2008). Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia.
    18. (2010). Non-B DNA structure-induced genetic instability and evolution.
    19. (1998). Parental gender, age at birth and expansion length influence GAA repeat intergenerational instability in the X25 gene: pedigree studies and analysis of sperm from patients with Friedreich’s ataxia.
    20. (1997). Phenotypic variability in Friedreich ataxia: role of the associated GAA triplet repeat expansion.
    21. (1995). Plasmid maintenance of derivatives of oriP of Epstein–Barr virus.
    22. (2009). Progressive GAA.TTC repeat expansion in human cell lines.
    23. (2007). Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia.
    24. (2003). Replication and expansion of trinucleotide repeats in yeast.
    25. (2001). Replication from oriP of Epstein–Barr virus requires human ORC and is inhibited by geminin.
    26. (1991). Replication initiates at multiple locations on an autonomously replicating plasmid in human cells.
    27. (2004). Replication stalling at Friedreich’s ataxia (GAA)n repeats in vivo.
    28. (2010). Replication-dependent instability at (CTG) x (CAG) repeat hairpins in human cells.
    29. (2004). Replication-mediated instability of the GAA triplet repeat mutation in Friedreich ataxia.
    30. (2009). Replisome stalling and stabilization at CGG repeats, which are responsible for chromosomal fragility.
    31. (2000). Ribosomal DNA replication fork barrier and HOT1 recombination hot spot: shared sequences but independent activities.
    32. (1995). Sea urchin zygote chromatin exhibit an unfolded nucleosomal array during the first S phase.
    33. (2003). Sequence-independent DNA binding and replication initiation by the human origin recognition complex.
    34. (2007). Somatic instability of the expanded GAA triplet-repeat sequence in Friedreich ataxia progresses throughout life.
    35. (1998). Sperm DNA analysis in a Friedreich ataxia premutation carrier suggests both meiotic and mitotic expansion in the FRDA gene.
    36. (2001). Sticky DNA, a self-associated complex formed at long GAA*TTC repeats in intron 1 of the frataxin gene, inhibits transcription.
    37. (1999). Sticky DNA: self-association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich’s ataxia.
    38. (1993). Suicidal nucleotide sequences for DNA polymerization.
    39. (2009). The chromatin signature of pluripotent cells,
    40. (1997). The effect of parental gender on the GAA dynamic mutation in the FRDA gene.
    41. (1989). The Epstein–Barr virus origin of plasmid replication, oriP, contains both the initiation and termination sites of DNA replication.
    42. (1997). The Friedreich ataxia GAA triplet repeat: premutation and normal alleles.
    43. (2002). The GAA triplet-repeat sequence in Friedreich ataxia shows a high level of somatic instability in vivo, with a significant predilection for large contractions.
    44. (2002). The molecular basis of Friedreich ataxia.
    45. (1996). The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia.
    46. (2000). Unexpected formation of parallel duplex in GAA and TTC trinucleotide repeats of Friedreich’s ataxia.
    47. (1996). Unwinding of the third strand of a DNA triple helix, a novel activity of the SV40 large T-antigen helicase.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.