title: The Replication of Frataxin Gene Is Assured by Activation of Dormant Origins in the Presence of a GAA-Repeat Expansion.
abstract: It is well known that DNA replication affects the stability of several trinucleotide repeats, but whether replication profiles of human loci carrying an expanded repeat differ from those of normal alleles is poorly understood in the endogenous context. We investigated this issue using cell lines from Friedreich's ataxia patients, homozygous for a GAA-repeat expansion in intron 1 of the Frataxin gene. By interphase, FISH we found that in comparison to the normal Frataxin sequence the replication of expanded alleles is slowed or delayed. According to molecular combing, origins never fired within the normal Frataxin allele. In contrast, in mutant alleles dormant origins are recruited within the gene, causing a switch of the prevalent fork direction through the expanded repeat. Furthermore, a global modification of the replication profile, involving origin choice and a differential distribution of unidirectional forks, was observed in the surrounding 850 kb region. These data provide a wide-view of the interplay of events occurring during replication of genes carrying an expanded repeat.
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Stevanoni
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Palumbo
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Antonella
authors.identifier: 0000-0001-6691-257X
authors.initials: A
authors.lastname: Russo
mesh_terms: D000483:Alleles; D002460:Cell Line; D004261:DNA Replication / Q000235:genetics*; D005621:Friedreich Ataxia / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007438:Introns; D033862:Iron-Binding Proteins / Q000235:genetics*; D008297:Male; D050505:Mutant Proteins / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D018911:Trinucleotide Repeats / Q000235:genetics; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D050505:Mutant Proteins; D000096923:Frataxin