The Replication of Frataxin Gene Is Assured by Activation of Dormant Origins in the Presence of a GAA-Repeat Expansion
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 fro...
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| description | 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. |
| doi_str_mv | 10.1371/journal.pgen.1006201 |
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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.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1006201</identifier><identifier>PMID: 27447727</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alleles ; Ataxia ; Biology and life sciences ; Cell Line ; Cloning ; Colleges & universities ; Deoxyribonucleic acid ; Disease ; DNA ; DNA probes ; DNA replication ; DNA Replication - genetics ; Expansion ; Experiments ; Frataxin ; Friedreich Ataxia - genetics ; Friedreich Ataxia - pathology ; Genes ; Genomes ; Humans ; Introns ; Iron-Binding Proteins - genetics ; Male ; Mutant Proteins - genetics ; Neuromuscular diseases ; Observations ; Properties ; Replication fork ; Research and Analysis Methods ; Trinucleotide Repeat Expansion - genetics ; Trinucleotide Repeats - genetics</subject><ispartof>PLoS genetics, 2016-07, Vol.12 (7), p.e1006201</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Gene Is Assured by Activation of Dormant Origins in the Presence of a GAA-Repeat Expansion. PLoS Genet 12(7): e1006201. doi:10.1371/journal.pgen.1006201</rights><rights>2016 Stevanoni et al 2016 Stevanoni et al</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Gene Is Assured by Activation of Dormant Origins in the Presence of a GAA-Repeat Expansion. 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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. 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| subjects | Alleles Ataxia Biology and life sciences Cell Line Cloning Colleges & universities Deoxyribonucleic acid Disease DNA DNA probes DNA replication DNA Replication - genetics Expansion Experiments Frataxin Friedreich Ataxia - genetics Friedreich Ataxia - pathology Genes Genomes Humans Introns Iron-Binding Proteins - genetics Male Mutant Proteins - genetics Neuromuscular diseases Observations Properties Replication fork Research and Analysis Methods Trinucleotide Repeat Expansion - genetics Trinucleotide Repeats - genetics |
| title | The Replication of Frataxin Gene Is Assured by Activation of Dormant Origins in the Presence of a GAA-Repeat Expansion |
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