Triplex H-DNA structure: the long and winding road from the discovery to its role in human disease.

H-DNA is an intramolecular DNA triplex formed by homopurine/homopyrimidine mirror repeats. Since its discovery, the field has advanced from characterizing the structure to discovering its existence and role . H-DNA interacts with cellular machinery in unique ways, stalling DNA and RNA polymerases and causing genome instability.

Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability.

Trinucleotide repeats, including Friedreich's ataxia (GAA) repeats, become pathogenic upon expansions during DNA replication and repair. Here, we show that deficiency of the essential replisome component Mcm10 dramatically elevates (GAA) repeat instability in a budding yeast model by loss of proper CMG helicase interaction. Supporting this conclusion, live-cell microscopy experiments reveal increased replication fork stalling at the repeat in mcm10-1 cells.

Replication dependent and independent mechanisms of GAA repeat instability.

Trinucleotide repeat instability is a driver of human disease. Large expansions of (GAA) repeats in the first intron of the FXN gene are the cause Friedreich's ataxia (FRDA), a progressive degenerative disorder which cannot yet be prevented or treated. (GAA) repeat instability arises during both replication-dependent processes, such as cell division and intergenerational transmission, as well as in terminally differentiated somatic tissues.

Aurora B activity is promoted by cooperation between discrete localization sites in budding yeast.

Chromosome biorientation is promoted by the four-member chromosomal passenger complex (CPC) through phosphorylation of incorrect kinetochore-microtubule attachments. During chromosome alignment, the CPC localizes to the inner centromere, the inner kinetochore, and spindle microtubules. Here we show that a small domain of the CPC subunit INCENP/Sli15 is required to target the complex to all three of these locations in budding yeast.

Rad9-mediated checkpoint activation is responsible for elevated expansions of GAA repeats in CST-deficient yeast.

Large-scale expansion of (GAA)n repeats in the first intron of the FXN gene is responsible for the severe neurodegenerative disease, Friedreich's ataxia in humans. We have previously conducted an unbiased genetic screen for GAA repeat instability in a yeast experimental system. The majority of genes that came from this screen encoded the components of DNA replication machinery, strongly implying that replication irregularities are at the heart of GAA repeat expansions.