2016
DOI: 10.1371/journal.pgen.1006201
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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 all… Show more

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Cited by 6 publications
(8 citation statements)
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“…These findings suggest that complex, multi-stranded RNA–DNA hybrid structures, which we call H-loops, might be instigators of HR at (GAA) n repeats. Given the fact that (GAA) n repeats have recently been shown to be replication barriers in human cell lines ( 24 , 75 ) and that R-loops appear to be involved in FXN silencing ( 20 ), our results contribute to the overall picture of R-loop formation in the pathobiology of FRDA.…”
Section: Discussionmentioning
confidence: 60%
“…These findings suggest that complex, multi-stranded RNA–DNA hybrid structures, which we call H-loops, might be instigators of HR at (GAA) n repeats. Given the fact that (GAA) n repeats have recently been shown to be replication barriers in human cell lines ( 24 , 75 ) and that R-loops appear to be involved in FXN silencing ( 20 ), our results contribute to the overall picture of R-loop formation in the pathobiology of FRDA.…”
Section: Discussionmentioning
confidence: 60%
“…Similarly, in samples from 15 tuberous sclerosis (TSC) patients in which deletions in the upstream TSC2 gene extended into PKD1, multiplex ligationdependent probe amplification (MLPA) did not show clustering of breakpoints near the IVS21 (Pu/Py)88 tract (62). One explanation for these observations may be a strong selection against PKD1 DSBs, which includes origin choice (151)(152)(153)(154) to avoid lagging strand replication of the PKD1 (Pu)88 sequence.…”
Section: Dsbs At the Structure-prone (Pu/py)88 Microsatellitementioning
confidence: 99%
“…No differences in terms of fork progression rate, inter origin distance (IOD), and cluster size were observed among the four cell lines (Figure 4A-D and Supplemental Table S2). 51,52 To investigate whether the large dNTP pools modify the tolerance of AGS cells to replication stress, as reported in yeast, 50 replication profiles of P2 and WT1 fibroblasts were assessed after treatment with aphidicolin (APH, 0.4 µM). 51,52 To investigate whether the large dNTP pools modify the tolerance of AGS cells to replication stress, as reported in yeast, 50 replication profiles of P2 and WT1 fibroblasts were assessed after treatment with aphidicolin (APH, 0.4 µM).…”
Section: Dna Replication Dynamics Is Unaffected In Ags Fibroblasts mentioning
confidence: 99%
“…Furthermore, the same frequencies of unidirectional forks and pause/arrest events were observed in all samples ( Supplemental Table S2) and fell within the ranges observed in other mammalian cells. 51,52 To investigate whether the large dNTP pools modify the tolerance of AGS cells to replication stress, as reported in yeast, 50 replication profiles of P2 and WT1 fibroblasts were assessed after treatment with aphidicolin (APH, 0.4 µM). As expected due to the inhibitory effect of APH on DNA replication, a significant reduction of fork rates, IOD and cluster size were observed in comparison to untreated samples, but no differential response was found between APH-treated P2 and WT1 cells ( Figure 4A-D and Supplemental Table S2).…”
Section: Dna Replication Dynamics Is Unaffected In Ags Fibroblasts mentioning
confidence: 99%