The roles of hNOC3 in DNA replication initiation in human cells and characterization of anticancer drug candidates

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, 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.

Date of Award	2019
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology