Publications by authors named "Alexandra N Khristich"
Recurrent DNA nicks drive massive expansions of (GAA) repeats.
Proc Natl Acad Sci U S A
December 2024
Article Synopsis
- Over 50 hereditary degenerative disorders are linked to the expansion of short tandem DNA repeats (STRs), especially (GAA) repeats, which are associated with diseases like Friedreich's ataxia.
- Researchers used a CRISPR-Cas9 nickase system to study the impact of introducing targeted DNA nicks near (GAA) repeats, discovering that nicks 5' of the repeat significantly boosted expansion rates and sizes in dividing cells.
- The study suggests that nicks can convert to double-strand breaks during DNA replication, resulting in repeat expansions, and also showed that 5' nicks can enhance expansion frequency in nondividing yeast cells, though less than in dividing cells.
Article Synopsis
- * Research on Friedreich's ataxia (GAA repeats) revealed that large-scale deletions and repeat expansions occur in nondividing cells during aging, driven by the activity of specific DNA repair complexes and polymerases.
- * The study highlights that the mechanisms of repeat instability differ significantly between dividing and non-dividing cells, suggesting these variations could impact the development of diseases like Friedreich's ataxia.
Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability.
View Article and Find Full Text PDFFriedreich's ataxia (FRDA) is a human hereditary disease caused by the presence of expanded (GAA) repeats in the first intron of the gene [V. Campuzano , 271, 1423-1427 (1996)]. In somatic tissues of FRDA patients, (GAA) repeat tracts are highly unstable, with contractions more common than expansions [R.
View Article and Find Full Text PDFExpansion of simple DNA repeats is responsible for numerous hereditary diseases in humans. The role of DNA replication, repair and transcription in the expansion process has been well documented. Here we analyzed, in a yeast experimental system, the role of RNA-DNA hybrids in genetic instability of long (GAA)n repeats, which cause Friedreich's ataxia.
View Article and Find Full Text PDFWe selected and investigated nine G-quadruplex (G4)-forming aptamers originally designed against different proteins involved in the regulation of cellular proliferation (STAT3, nucleolin, TOP1, SP1, VEGF, and SHP-2) and considered to be potential anticancer agents. We showed that under physiological conditions all the aptamers form stable G4s of different topology. G4 aptamers designed against STAT3, nucleolin and SP1 inhibit STAT3 transcriptional activity in human breast adenocarcinoma MCF-7 cells, and all the studied aptamers inhibit TOP1-mediated relaxation of supercoiled plasmid DNA.
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