DNA replication is fundamental for cell proliferation in all organisms. Nonetheless, components of the replisome have been implicated in human disease, and here we report encoding the catalytic subunit of DNA primase as a novel disease gene. Using a variant classification agnostic approach, biallelic mutations in PRIM1 were identified in five individuals. PRIM1 protein levels were markedly reduced in patient cells, accompanied by replication fork asymmetry, increased interorigin distances, replication stress, and prolonged S-phase duration. Consequently, cell proliferation was markedly impaired, explaining the patients' extreme growth failure. Notably, phenotypic features distinct from those previously reported with DNA polymerase genes were evident, highlighting differing developmental requirements for this core replisome component that warrant future investigation.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608753PMC
http://dx.doi.org/10.1101/gad.340190.120DOI Listing

Publication Analysis

Top Keywords

cell proliferation
8
prim1 deficiency
4
deficiency distinctive
4
distinctive primordial
4
primordial dwarfism
4
dwarfism syndrome
4
syndrome dna
4
dna replication
4
replication fundamental
4
fundamental cell
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!