| Abstract |
Helicases process the double-stranded DNA dissociation. They are involved
in replication, DNA repair and maintenance of telomeres. In human, 3
helicases display mutations responsible for clinical syndromes: WRN for
the Werner syndrome, BLM for the Bloom syndrome and RECQL4 for the
Rothmund-Thomson syndrome. All these diseases cause premature ageing and
high risk of cancer. Molecular and cellular mechanisms involved in these
diseases are not well defined. Particularly, little is known concerning
the link between genomic instability and ageing. During this project, we
used blood samples and skin biopsies of affected patients to generate
models by reprogramming cells to induced pluripotent stem cells (iPSCs).
These cells have the advantage of self-renewing and theoretically could be
differentiated in all cell types. At the same time, an iPSC senescence
control was performed from cells of a Hutchinson-Gilford Progeria syndrome
patient. iPSCs were characterized for pluripotency. In the aim of
recapitulate these pathologies in vitro, we identified sets of cellular
and molecular phenotypes. We also engaged differentiation of iPSCs in cell
pathways closed to the affected tissues in vivo. Finally, we studied the
genomic stability of iPSCs and derived cells. We observed that Bloom cells
are susceptible to frequent recombinations and are characterized by a
genome instability through all studied cell types. Werner cells showed an
instability of telomeres length. Finally, all premature ageing diseases
displayed mitochondrial defects.
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