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Seminar

Tuesday, April 17th, 2018
11h30
Centre de Recherche - Orsay - Amphithéâtre du Bâtiment 111

Chromosome integrity compromised by expanded GAA/TTC tracts: the interplay between transcription, R loops and replication

Triplex-forming GAA/TTC repeat tracts belong to a class of trinucleotide repeats that are associated with a growing number of neurological diseases known collectively as the Repeat Expansion Diseases.  GAA/TTC repeats are a common sequence motif abundant in mammalian genomes including humans where ~2,500 GAA/TTC loci were identified.  Repeat tracts can both contract and expand; the latter feature is responsible for the spreading of repressive chromatin that inactivates the FXN gene in Friedreich’s ataxia patients.  The repeats are unstable in both proliferating and terminally differentiated cells such as neuronal cells.  Studies in my and other laboratories revealed that in yeast, plants and humans, GAA/TTC-mediated breaks lead to gross chromosomal rearrangements, crossing-over, and mutagenesis.  Using yeast, we discovered that expanded tracts behave as a canonical fragile site that is expressed upon replication stress.  Remarkably, in nondividing cells, GAA/TTC tracts have even higher DSB-inducing potential making them a unique example of the endogenous source of breakage and chromosomal aberrations operating outside of S-phase.  I will present an evidence that abnormal transcription intermediates initiated inside tracts is a major factor, responsible for detrimental consequences of GAA/TTC instability in both actively dividing and nondividing cells.  I will also describe our findings on key regulators of the repeat instability. Finally, I will extrapolate the results obtained in the yeast model system to mechanisms that mediate detrimental metabolism of GAA/TTC tracts in human cells

Event poster

Speaker(s)

Dr. Kirill Lobachev
Department of Biology

Department of Biology, Georgia Institute of Technology

Invited by

Sarah Lambert
Domain 1 - UMR 3348 - Genotoxic Stress and Cancer

Institut Curie

Contact

Sarah Lambert

Institut Curie

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