Thesis (Ph. D.)--Oregon State University, 2000. / Typescript (photocopy). Includes bibliographical references (leaves 72-73). Also available on the World Wide Web.

Thesis (Ph. D.)--University of Wisconsin, 1966. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin, 1966. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliography.

Dans le noyau des cellules eucaryotes, l’ADN est associé aux histones pour former la chromatine. Les extrémités terminales des histones peuvent subir un grand nombre de modifications posttraductionnelles réversibles (méthylation, acétylation, phosphorylation, ubiquitinylation…). Certaines de ces marques épigénétiques définissent des domaines chromatiniens particuliers du noyau. Les triméthylations des lysines 9 et 27 de l’histone H3 (H3K9me3 et H3K27me3) correspondent respectivement à des domaines d’hétérochromatine constitutive et d’hétérochromatine facultative. Les proteines qui possèdent un chromo-domaine sont capables de se lier à des lysines méthylées, et permettent de recruter des complexes qui ont une activité enzymatique ou mécanique sur la chromatine. Les protéines de la famille CBX (ChromoBoX) possèdent toutes un chromodomaine, elles sont subdivisées en 2 groupes: les protéines du groupe HP1 (CBX1, CBX3 et CBX5) et celles du groupe Polycomb (CBX2, CBX4, CBX6, CBX7 et CBX8) qui se fixent respectivement sur H3K9me3 et H3K27me3, respectivement. Afin de mieux comprendre comment s’organise la chromatine au niveau des régions hétérochromatiques, nous avons purifié, en condition native, les complexes associés à ces 8 protéines dans des cellules humaines en culture. Pour ce faire, nous avons opté pour la purification d’affinité en tandem (TAP). Les protéines co-éluées ont été identifiées par spectrométrie de masse. Nos résultats confirment que, d’une part les protéines du groupe Polycomb sont associées au complexe PRC1 (Polycomb Repressive Complex 1). Toutefois, ces protéines sont mutuellement exclusives au sein du complexe PRC1, indiquant qu’il existe plusieurs complexes PRC1 de composition distincte dans la cellule. D’autre part, de nouveaux partenaires associés aux protéines du groupe HP1 ont été identifiés. La mise au point et le développement de la technologie TAP sur des cellules humaines en culture nous ont permis de purifier des complexes associés à la chromatine. Cette technique demeure un outil biochimique efficace pour la purification de complexes protéiques / In the nucleus of eukaryotic cells, DNA is wrapped around histones to form chromatin. The terminal ends of histones may undergo many reversible post-translational modifications (methylation, acetylation, phosphorylation, ubiquitinylation...). Some of these epigenetic marks define specific chromatic regions in the nucleus. The tri-methylation of lysines 9 and 27 of histone H3 (H3K9me3 and H3K27me3) correspond respectively to constitutive and facultative heterochromatin. Chromo-domain containing proteins can bind to methylated lysines, and can recruit complexes having enzymatic or mechanical activity on chromatin. All the members of the CBX (ChromoBoX) family contain a chromodomain, they are divided into 2 groups: the HP1 group (CBX1, CBX3 and CBX5) and the Polycomb group (CBX2, CBX4, CBX6, CBX7 and CBX8) able to bind to H3K9me3 and H3K27me3, respectively. To better understand how the chromatin is organized in heterochromatic regions we purified, in native condition, the complexes associated with these 8 proteins from human cells in culture. To this end, we opted for the tandem affinity purification (TAP). The co-eluted proteins were identified by mass spectrometry. Our results confirm that firstly, Polycomb group proteins are involved in PRC1 complex (Polycomb Repressive Complex 1). However, these proteins are mutually exclusive in the PRC1 complex, indicating that several PRC1 of distinct compositions co-exist in the cell. On the other hand, new partners associated with HP1 group were identified. The development of the TAP technology to cultured human cells allowed us to purify complexes associated with chromatin. This technique remains an effective tool for the biochemical purification of protein complexes.

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Thesis (M. Phil.)--University of Hong Kong, 1999. / Includes bibliographical references.

Yes / Platinum drugs are widely used for cancer treatment. Other precious metals are promising, but their clinical progress depends on achieving different mechanisms of action to overcome Pt-resistance. Here, we evaluate 13 organo-Os complexes: 16-electron sulfonyl-diamine catalysts [(η6-arene)Os(N,N′)], and 18-electron phenylazopyridine complexes [(η6-arene)Os(N,N’)Cl/I]+ (arene = p-cymene, biphenyl, or terphenyl). Their antiproliferative activity does not depend on p21 or p53 status, unlike cisplatin, and their selective potency toward cancer cells involves the generation of reactive oxygen species. Evidence of such a mechanism of action has been found both in vitro and in vivo. This work appears to provide the first study of osmium complexes in the zebrafish model, which has been shown to closely model toxicity in humans. A fluorescent osmium complex, derived from a lead compound, was employed to confirm internalization of the complex, visualize in vivo distribution, and confirm colocalization with reactive oxygen species generated in zebrafish. / Wellcome Trust (grant no. 107691/Z/15/Z), ERC (grant nos. 247450, 324594), Science City (AWM and ERDF), WCPRS and Bruker Daltonics (Studentship for JPCC), Mike and Enfys Bagguley, and EPSRC (Studentship for HEB, and grant no. EP/F034210/1)