Spotlight on the Replisome: Aetiology of DNA Replication-Associated Genetic Diseases.

Human development and tissue homeostasis depend on the regulated control of cellular proliferation and differentiation. DNA replication is essential to couple genome duplication and cell division with the establishment and maintenance of cellular differentiation programs. In eukaryotes, DNA replication is performed by a large machine known as the 'replisome,' which is strictly regulated in a cell cycle-dependent manner. Inherited mutations of replisome components have been identified in a range of genetic conditions characterised by developmental abnormalities and reduced organismal growth in addition to an involvement of the immune and endocrine systems and/or heightened tumour predisposition. Here, we review the current knowledge of the molecular genetics of replisome dysfunction disorders and discuss recent mechanistic insights into their pathogenesis, with a focus on the specific steps of DNA replication affected in these human diseases. DNA replication is performed by a multiprotein complex known as the 'replisome,' which is assembled and regulated in a cell cycle–dependent manner. Hypomorphic mutations of components of the replisome lead to defective development, reduced growth, and altered tissue homeostasis. Whole-genome sequencing studies significantly expanded the repertoire of mendelian diseases caused by mutation of the replication machinery. Phenotypic analysis and mechanistic studies support defective replication origin assembly and activation and perturbation of replication fork stability as the pathogenetic mechanisms of replication-linked human genetic diseases. [ABSTRACT FROM AUTHOR]