Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms

Abstract

Deoxyribonucleic acid (DNA) replication can be divided into three major steps: initiation, elongation and termination. Each time a human cell divides, these steps must be reiteratively carried out. Disruption of DNA replication can lead to genomic instability, with the accumulation of point mutations or larger chromosomal anomalies such as rearrangements. While cancer is the most common class of disease associated with genomic instability, several congenital diseases with dysfunctional DNA replication give rise to similar DNA alterations. In this review, we discuss all congenital diseases that arise from pathogenic variants in essential replication genes across the spectrum of aberrant replisome assembly, origin activation and DNA synthesis. For each of these conditions, we describe their clinical phenotypes as well as molecular studies aimed at determining the functional mechanisms of disease, including the assessment of genomic stability. By comparing and contrasting these diseases, we hope to illuminate how the disruption of DNA replication at distinct steps affects human health in a surprisingly cell-type-specific manner.

WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage

“…Because genome-instability is a hallmark of cancer, the findings described here support a previously proposed model that WASp functions within the “tumor-suppressor” apparatus in normal lymphocytes 49 , and that its loss triggers replication dysfunction and genome-instability contributing to oncogenesis in WAS. Notably, immunodeficiencies frequently occur in certain congenital diseases arising from mutations in essential replication genes 50 . In this connection, multiple WAS mutations/ variants (p.D485G; p.E486K; p.D489N; p.D493N; p.D497E; pD497Y) are reported in the public WAS-databases that occur in/or around RBM1, which could potentially disrupt RPA1-activity directly.…”

De novo 22q11.2 deletions and auricular findings in two Chinese patients with microtia

“…The region encompasses three candidate genes involved in pharyngeal arches development, including HIC2, YPEL1, and MAPK1. However, the typical auricular phenotype in these patients is preauricular tags but not microtia (Schmit & Bielinsky, 2021). One OAVS patient with central 22q11.2 deletion between LCR22B-D was reported.…”

“…The loss of cell division cycle 45 gene (CDC45, MIM *603465) embedded in 22q11.2 has been reported to be related to craniofacial malformations, as in Meier-Gorlin syndrome and craniosynostosis (Miller et al, 2017;Parker et al, 2018). As one of the components in replicative helicase Cdc45-MCM2-7-GINS (CMG), CDC45 functions in DNA replication which is crucial in many developmental processes (Schmit & Bielinsky, 2021;Tognetti et al, 2015). We therefore speculate that the loss of CDC45 on 22q11.2 is an important causal mutation for ear malformation.…”

Human RecQL4 as a Novel Molecular Target for Cancer Therapy

“…Nevertheless, it is widely accepted that acquisition and sustenance of an infinite replicative potential are key factors for carcinogenesis. Retarded growth potential of human cells deficient in BLM, WRN, and RecQL4 gave a general indication that RecQ helicases participate in DNA replication [Bennett and Keck, 2004;Burla et al, 2018;Schmit and Bielinsky, 2021]. Since this review is focused on RecQL4, much of the discussion is confined only to RecQL4 and its associated activities in DNA replication.…”