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© Research
Project

Mini and Microsatellite instabilities

Scientific Fields
Diseases
Organisms
Applications
Technique
Starting Date
09
Jun 2015
Status
Ongoing
Members
2

About

Guy-Franck Richard, Alix Kerrest

We are interested in understanding how DNA tandem repeats, like microsatellites and minisatellites are born, evolve and disappear. Trinucleotide repeats, a particular class of microsatellites, are involved in a growing number of human neurological disorders, including X-fragile, Huntington disease and several types of ataxias. The pathology is always associated to the large expansion of a trinucleotide repeat within or near a gene. We have shown that these expansions, in yeast, occur both during DNA replication and homologous recombination. We have isolated two genes, SGS1 and SRS2 (encoding DNA helicases conserved from bacteria to humans) that are involved in stabilizing trinucleotide repeats. We now try to understand the tight links between replication and homologous recombination and how these two metabolic pathways interact with each other.

Minisatellites are longer tandem repeats, also found in all eukaryotic genomes. By comparative genomics, we have shown that they evolve faster than the genes containing them. The mechanisms underlying birth, fast evolution and death of minisatellites are currently under investigation.

Our main questions are:

  1. How do DNA helicases interplay in stabilizing tandem repeats in vivo?
  2. How do replication and homologous recombination interact with each other during the cell cycle?
  3. What are the molecular mechanisms involved in the de novo formation of tandem repeats?

In order to adress these questions, we use classical reverse genetics and molecular biology approaches, such as conditional mutants, DNA two-dimensional gel electrophoreses and chromatin immunoprecipitation.

xx
A model showing three different pathways to repair replication fork-damage due to trinucleotide repeat-dependent structures. Top: Srs2 and Sgs1 helicases act at the fork to facilitate replication across structure-forming sequences. In the absence of either of these helicases, single-strand gaps or double-strand breaks result Left arrow: Srs2p can also facilitate fork regression, perhaps by removing Rad51 from damaged forks, to allow bypass of the damage and fork restart in a manner that prevents breakage and repeat length changes. Middle downward arrows: Single-strand or double-strand breaks can be processed by a Rad51-dependent sister chromatid recombination pathway, leading to recombination intermediates that are dissolved by Sgs1p-Top3p. Hairpin formation by CAG/CTG repeats during strand invasion can lead to repeat contractions or expansions depending on the location of the hairpin. Joint molecules observed by 2D gels (shown inside the grey box) correspond to either regressed forks or Rad51-dependent sister chromatid recombination intermediates.