Paediatrics (RCH) - Theses
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ItemFunctional analysis of a novel mammalian zinc-finger centromere protein, ZNF397( 2010)The centromere is responsible for ensuring correct segregation of newly replicated sister chromatids into daughter cells. This fundamental role is conserved in eukaryotic organisms from yeast to humans. An error in chromosome segregation, including mutations in proteins that have a role in the assembly of the kinetochore, can result in daughter cells with an abnormal chromosomal number (aneuploidy). In humans, aneuploidy is a major contributor to birth defects, spontaneous abortions and infertility (Hassold and Hunt 2001), and is often associated with cancer due to the loss of tumour-suppressor genes or gain of oncogenes. A novel centromere protein, ZNF397, has recently been identified using a centromere positive autoimmune serum from a patient with watermelon stomach disease. ZNF397 protein belongs to the classical C2H2 group of the zinc-finger protein superfamily, which is one of the largest families in the human proteome. It contains two conserved domains; a leucine-rich SCAN domain and nine C2H2 zinc fingers. Bioinformatic analysis showed that ZNF397 is conserved in placental mammals. To date, only a few proteins containing zinc-finger domains have been identified at the centromeric or pericentric loci in various eukaryotic organisms. Stable human cell lines expressing a green fluorescent protein-ZNF397 fusion demonstrated that ZNF397 was centromeric and it co-localised with constitutive centromere protein CENP-A during interphase to early prophase of human cells. Deletion and domain-swap constructs indicated that the SCAN domain was necessary, but not sufficient, for centromere localisation. ZNF397 also localised to an active neocentromere, not the inactive α-satellite centromere on a pseudo-dicentric neocentromere chromosome four. Knockout studies in mice have revealed that ZNF397 was not essential for chromosome segregation, development or reproduction of the mice. The presence of ZNF397 in interphase cells but not on mitotic chromosomes suggests that it is not a constitutive structural protein and that it is unlikely to be directly involved in microtubule capture, mitotic segregation, or cytokinesis. An attractive hypothesis is that ZNF397 plays a role in the regulation of transcription at the centromere. Two possible mechanisms of action for ZNF397 are proposed; 1) ZNF397 could be directly involved in transcription of centromeric repeats or 2) ZNF397 could repress genes by recruiting them to the centromeric heterochromatin environment.