The Replication of Frataxin Gene Is Assured by Activation of Dormant Origins in the Presence of a GAA-Repeat Expansion.
Martina StevanoniElisa PalumboAntonella RussoPublished in: PLoS genetics (2016)
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.
Keyphrases
- genome wide
- genome wide identification
- copy number
- end stage renal disease
- endothelial cells
- newly diagnosed
- dna methylation
- ejection fraction
- magnetic resonance imaging
- peritoneal dialysis
- early onset
- computed tomography
- gene expression
- machine learning
- deep learning
- big data
- mass spectrometry
- decision making
- contrast enhanced
- induced pluripotent stem cells
- data analysis
- wild type