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.

Automated summary

Cellular proliferation and differentiation are dependent on regulated DNA replication by the replisome, a large machine in eukaryotes. Mutations in replisome components can lead to genetic disorders characterized by developmental abnormalities, reduced organismal growth, and heightened tumour predisposition. Understanding the molecular genetics and pathogenesis of these disorders is crucial for developing targeted therapies.