Caractérisation phénotypique et moléculaire de déficiences humaines liées à des dysfonctions des télomères et / ou de la réparation de l’ADN

Abstract : Maintaining genome integrity is essential for cell survival and propagation of the genetic information. Improper management of DNA damages and / or aberrations in maintenance of telomere - the ends of linear chromosomes - causes humans disorders associated with genetic instability. Thus, in humans, telomere dysfunction causes Dyskeratosis Congenita (DC), and its rare and severe form, Hoyeraal-Hreidarsson Syndrome (HHS). DC and HHS are mainly characterized by progressive bone marrow failure, developmental defects and predisposition to cancer. In addition, many syndromes involving immunodeficiency and developmental abnormalities are caused by defects in DNA repair (e.g. severe immune deficiencies, Fanconi Anemia (FA), Ataxia Telangiectasia (AT),…). In this work, we performed a phenotypic and genetic study of patients with two syndromes presenting distinct clinical features. This work permitted : 1) on one hand, to identify RTEL1 mutations in patients with HHS and describe a new molecular cause of this disease. The analysis of patients’ cells revealed the crucial role for RTEL1 in genome stability and telomere maintenance in human cells. 2) on the other hand, to identify mutations in MYSM1, a histone deubiquitinase, in a new immuno-hematological syndrome associated with defects in DNA repair and sharing some similarities with Fanconi anemia. This study demonstrates for the first time that, in addition to its role in transcriptional regulation, MYSM1 is required to cope with DNA damages.
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Tangui Le Guen. Caractérisation phénotypique et moléculaire de déficiences humaines liées à des dysfonctions des télomères et / ou de la réparation de l’ADN. Médecine humaine et pathologie. Université René Descartes - Paris V, 2013. Français. ⟨NNT : 2013PA05T092⟩. ⟨tel-01124184⟩

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