THESIS
2019
xi, 147 pages : illustrations (some color) ; 30 cm
Abstract
Noc3p (Nucleolar complex associated protein 3) was first identified in budding yeast for its
function in ribosome biogenesis and later reported by our lab to be also involved in the assembly
of the pre-replicative complex (pre-RC). It interacts with multiple pre-RC proteins including
subunits of the origin recognition complex (ORC) and minichromosome maintenance (MCM)
complex and is necessary for the recruitment of Cdc6p and MCM proteins onto the chromatin
during pre-RC assembly. Depletion of Noc3p impairs pre-RC assembly, hence DNA replication
and proliferation in yeast.
FAD24 (Factor for adipocyte differentiation, clone 24) was found to be the human homolog of
Noc3p by sequence homology. It was previously reported to be necessary for DNA replication, cell
cycle re-entry, prol...[
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Noc3p (Nucleolar complex associated protein 3) was first identified in budding yeast for its
function in ribosome biogenesis and later reported by our lab to be also involved in the assembly
of the pre-replicative complex (pre-RC). It interacts with multiple pre-RC proteins including
subunits of the origin recognition complex (ORC) and minichromosome maintenance (MCM)
complex and is necessary for the recruitment of Cdc6p and MCM proteins onto the chromatin
during pre-RC assembly. Depletion of Noc3p impairs pre-RC assembly, hence DNA replication
and proliferation in yeast.
FAD24 (Factor for adipocyte differentiation, clone 24) was found to be the human homolog of
Noc3p by sequence homology. It was previously reported to be necessary for DNA replication, cell
cycle re-entry, proliferation, and adipogenesis in human cells. In this project, we aimed to
investigate how NOC3 regulates DNA replication in human cells. The results suggest that human
NOC3 is involved in pre-RC assembly, DNA replication, cell proliferation and survival in human cells, independent of its potential function in ribosome biogenesis.
We are currently screening for small molecules that potentially target the pre-RC as an anticancer strategy. A compound nicknamed M2 was found to have significant anticancer activities by
inhibiting DNA replication, with a lower toxicity towards normal cells. The screening is still in
progress and we have identified more candidates. Cell cycle analysis and mechanistic studies have
been performed for M2 and the newly identified compounds.
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