54 research outputs found
Current use of noninvasive prenatal testing in Europe, Australia and the USA : A graphical presentation
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Pathologies of helicases and premature aging : study by derivation of induced pluripotent stem cells
Les hĂ©licases sont des enzymes ubiquitaires catalysant la sĂ©paration de lâADN double-brin et impliquĂ©es dans la rĂ©plication, la rĂ©paration de lâADN et dans le maintien des tĂ©lomĂšres. Chez lâHomme, 3 hĂ©licases prĂ©sentent des mutations responsables de syndromes cliniques : WRN pour le syndrome de Werner, BLM pour le syndrome de Bloom et RECQL4 pour le syndrome de Rothmund-Thomson. Tous ces syndromes associent un vieillissement pathologique accĂ©lĂ©rĂ© Ă un risque accru de dĂ©veloppement de cancer notamment par une augmentation de lâinstabilitĂ© gĂ©nomique. Les connaissances sur les mĂ©canismes molĂ©culaires et cellulaires impliquĂ©s dans ces maladies du vieillissement sont encore trĂšs partielles, notamment en ce qui concerne le lien entre lâinstabilitĂ© gĂ©nomique et le vieillissement. Au cours de ce projet, l'utilisation de prĂ©lĂšvements sanguins et cutanĂ©s de patients atteints de ces pathologies rares a permis de gĂ©nĂ©rer des modĂšles de cellules souches pluripotentes induites (iPS). Ces cellules prĂ©sentent lâavantage de sâauto-renouveler et de pouvoir thĂ©oriquement se diffĂ©rencier dans tous les types cellulaires dâun organisme. ParallĂšlement, un tĂ©moin de sĂ©nescence a Ă©tĂ© gĂ©nĂ©rĂ© de la mĂȘme maniĂšre avec des cellules dâun patient souffrant du syndrome de la progĂ©ria de Hutchinson-Gilford. AprĂšs caractĂ©risation de ces cellules, nous avons identifiĂ© des ensembles de phĂ©notypes cellulaires et molĂ©culaires dans le but de rĂ©capituler in vitro les pathologies. Nous avons Ă©galement engagĂ© les cellules iPS dans des voies de diffĂ©renciation proches des tissus atteints dans les pathologies in vivo. Enfin, nous avons Ă©tudiĂ© la stabilitĂ© gĂ©nomique de ces lignĂ©es dans les diffĂ©rents types cellulaires cultivĂ©s. Ainsi nous avons observĂ© que la lignĂ©e Bloom est le siĂšge de recombinaisons particuliĂšrement frĂ©quentes et est caractĂ©risĂ©e par une instabilitĂ© du gĂ©nome dans tous les types cellulaires Ă©tudiĂ©s. Egalement, la lignĂ©e Werner semblerait se distinguer par une instabilitĂ© de ses tĂ©lomĂšres. Enfin, lâensemble des lignĂ©es des pathologies du vieillissement prĂ©maturĂ© prĂ©senterait un dĂ©faut mitochondrial.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
Pathologies des hélicases et vieillissement précoce : modÚle d'étude par dérivation de cellules souches pluripotentes induites (iPS)
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.Les hĂ©licases sont des enzymes ubiquitaires catalysant la sĂ©paration de lâADN double-brin et impliquĂ©es dans la rĂ©plication, la rĂ©paration de lâADN et dans le maintien des tĂ©lomĂšres. Chez lâHomme, 3 hĂ©licases prĂ©sentent des mutations responsables de syndromes cliniques : WRN pour le syndrome de Werner, BLM pour le syndrome de Bloom et RECQL4 pour le syndrome de Rothmund-Thomson. Tous ces syndromes associent un vieillissement pathologique accĂ©lĂ©rĂ© Ă un risque accru de dĂ©veloppement de cancer notamment par une augmentation de lâinstabilitĂ© gĂ©nomique. Les connaissances sur les mĂ©canismes molĂ©culaires et cellulaires impliquĂ©s dans ces maladies du vieillissement sont encore trĂšs partielles, notamment en ce qui concerne le lien entre lâinstabilitĂ© gĂ©nomique et le vieillissement. Au cours de ce projet, l'utilisation de prĂ©lĂšvements sanguins et cutanĂ©s de patients atteints de ces pathologies rares a permis de gĂ©nĂ©rer des modĂšles de cellules souches pluripotentes induites (iPS). Ces cellules prĂ©sentent lâavantage de sâauto-renouveler et de pouvoir thĂ©oriquement se diffĂ©rencier dans tous les types cellulaires dâun organisme. ParallĂšlement, un tĂ©moin de sĂ©nescence a Ă©tĂ© gĂ©nĂ©rĂ© de la mĂȘme maniĂšre avec des cellules dâun patient souffrant du syndrome de la progĂ©ria de Hutchinson-Gilford. AprĂšs caractĂ©risation de ces cellules, nous avons identifiĂ© des ensembles de phĂ©notypes cellulaires et molĂ©culaires dans le but de rĂ©capituler in vitro les pathologies. Nous avons Ă©galement engagĂ© les cellules iPS dans des voies de diffĂ©renciation proches des tissus atteints dans les pathologies in vivo. Enfin, nous avons Ă©tudiĂ© la stabilitĂ© gĂ©nomique de ces lignĂ©es dans les diffĂ©rents types cellulaires cultivĂ©s. Ainsi nous avons observĂ© que la lignĂ©e Bloom est le siĂšge de recombinaisons particuliĂšrement frĂ©quentes et est caractĂ©risĂ©e par une instabilitĂ© du gĂ©nome dans tous les types cellulaires Ă©tudiĂ©s. Egalement, la lignĂ©e Werner semblerait se distinguer par une instabilitĂ© de ses tĂ©lomĂšres. Enfin, lâensemble des lignĂ©es des pathologies du vieillissement prĂ©maturĂ© prĂ©senterait un dĂ©faut mitochondrial
Chromoanagenesis: a piece of the macroevolution scenario
Over the last decade, new types of massive and complex chromosomal rearrangements based on the chaotic shattering and restructuring of chromosomes have been identified in cancer cells as well as in patients with congenital diseases and healthy individuals. These unanticipated phenomena are named chromothripsis, chromoanasynthesis and chromoplexy, and are grouped under the term of chromoanagenesis. As mechanisms for rapid and profound genome modifications in germlines and early development, these processes can be regarded as credible pathways for genomic evolution and speciation process. Their discovery confirms the importance of genome-centric investigations to fully understand organismal evolution. Because they oppose the model of progressive acquisition of driver mutations or rearrangements, these phenomena conceptually give support to the concept of macroevolution, known through the models of "Hopeful Monsters" and the "Punctuated Equilibrium". In this review, we summarize mechanisms underlying chromoanagenesis processes and we show that numerous cases of chromosomal speciation and short-term adaptation could be correlated to chromoanagenesis-related mechanisms. In the frame of a modern and integrative analysis of eukaryote evolutionary processes, it seems important to consider the unexpected chromoanagenesis phenomena.status: publishe
Chromoanagenesis: a piece of the macroevolution scenario
International audienceOver the last decade, new types of massive and complex chromosomal rearrangements based on the chaotic shattering and restructuring of chromosomes have been identified in cancer cells as well as in patients with congenital diseases and healthy individuals. These unanticipated phenomena are named chromothripsis, chromoanasynthesis and chromoplexy, and are grouped under the term of chromoanagenesis. As mechanisms for rapid and profound genome modifications in germlines and early development, these processes can be regarded as credible pathways for genomic evolution and speciation process. Their discovery confirms the importance of genome-centric investigations to fully understand organismal evolution. Because they oppose the model of progressive acquisition of driver mutations or rearrangements, these phenomena conceptually give support to the concept of macroevolution, known through the models of âHopeful Monstersâ and the âPunctuated Equilibriumâ. In this review, we summarize mechanisms underlying chromoanagenesis processes and we show that numerous cases of chromosomal speciation and short-term adaptation could be correlated to chromoanagenesis-related mechanisms. In the frame of a modern and integrative analysis of eukaryote evolutionary processes, it seems important to consider the unexpected chromoanagenesis phenomena
Potential Role of Chromothripsis in the Genesis of Complex Chromosomal Rearrangements in Human Gametes and Preimplantation Embryo.
International audienceThe discovery of a new class of massive chromosomal rearrangement, baptized chromothripsis, in different cancers and congenital disorders has deeply modified our understanding on the genesis of complex genomic rearrangements. Several mechanisms, involving abortive apoptosis, telomere erosion, mitotic errors, micronuclei formation, and p53 inactivation, might cause chromothripsis. The remarkable point is that all these plausible mechanisms have been identified in the field of human reproduction as causal factors for reproductive failures and chromosomal abnormality genesis. Specific features of gametogenesis and early embryonic development may contribute to the emergence of chromothripsis. Multiple lines of evidence support the assumption that chromothripsis may arise more frequently than previously thought in both gametogenesis and early human embryogenesis
Effect of adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) hull extracts on testosterone release from rat Leydig cells.
International audienceChromoanasynthesis has been described as a novel cause of massive constitutional chromosomal rearrangements. Based on DNA replication machinery defects, chromoanasynthesis is characterized by the presence of chromosomal duplications and triplications locally clustered on one single chromosome, or a few chromosomes, associated with various other types of structural rearrangements. Two distinct mechanisms have been described for the formation of these chaotic genomic disorders, i.e. the fork stalling and template switching and the microhomology-mediated break-induced replication. Micronucleus-based processes have been evidenced as a causative mechanism, thus, highlighting the close connection between segregation errors and structural rearrangements. Accumulating data indicate that chromoanasynthesis is operating in human germline cells and during early embryonic development. The development of new tools for quantifying chromoanasynthesis events should provide further insight into the impact of this catastrophic cellular phenomenon in human reproduction
Les réarrangements chromosomiques complexes (du chromosome à la molécule: développement de deux approches méthodologiques pour la caractérisation des points de cassure)
MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF
Le
La dĂ©couverte rĂ©cente, dans diffĂ©rents cancers, dâun nouveau type de remaniements chromosomiques massifs, baptisĂ©s chromothripsis (du grec chromo pour chromosome, et thripsis pour briser en Ă©clat), bouleverse les modĂšles Ă©tablis de dĂ©veloppement progressif des tumeurs. En effet, ce phĂ©nomĂšne se caractĂ©rise par la pulvĂ©risation dâun (ou de quelques) segment(s) chromosomique(s) et le rĂ©assemblage alĂ©atoire des fragments chromosomiques gĂ©nĂ©rĂ©s, et se produit au cours dâun seul Ă©vĂ©nement cellulaire. Le mĂȘme phĂ©nomĂšne a Ă©tĂ© identifiĂ© en gĂ©nĂ©tique constitutionnelle chez des patients atteints de diverses pathologies du dĂ©veloppement, indiquant que le chromothripsis survient aussi au niveau germinal. Les causes du chromothripsis sont variĂ©es : radiations, Ă©rosion tĂ©lomĂ©rique, apoptose abortive, etc. Deux voies de rĂ©paration « express » du gĂ©nome sont utilisĂ©es par la cellule pour restructurer de maniĂšre chaotique les rĂ©gions chromosomiques concernĂ©es : les mĂ©canismes de jonction des extrĂ©mitĂ©s non homologues et la rĂ©paration par stress rĂ©plicatif. LâĂ©tude approfondie des sĂ©quences dâADN des zones de chromothripsis permet dĂ©sormais de mieux cerner la signature molĂ©culaire de ce processus et de mieux apprĂ©hender son rĂŽle, jusquâalors insoupçonnĂ©, dans le dĂ©veloppement de pathologies congĂ©nitales et la progression des cancers
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