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Multiple modes of DNA repair need DNA synthesis by DNA polymerase enzymes. The eukaryotic B-family DNA polymerase complexes delta (Polδ) and zeta (Polζ) help to repair DNA strand breaks when primed by homologous recombination or single-strand DNA annealing. DNA synthesis by Polδ and Polζ is mutagenic, but is needed for the survival of cells in the presence of DNA strand breaks. The POLD3 subunit of Polδ and Polζ is at the heart of DNA repair by recombination, by modulating polymerase functions and interacting with other DNA repair proteins. We provide the background to POLD3 discovery, investigate its structure, as well as function in cells. We highlight unexplored structural aspects of POLD3 and new biochemical data that will help to understand the pivotal role of POLD3 in DNA repair and mutagenesis in eukaryotes, and its impact on human health. [ABSTRACT FROM AUTHOR]

Human DDX49 is an emerging target in cancer progression and retroviral diseases through its essential roles in nucleolar RNA processing. Here, we identify nuclease activity of human DDX49, which requires active site aspartate residues within a conserved region of metazoan DDX49s that is absent from yeast and archaeal DDX49 homologues. We provide evidence that DDX49 nuclease activity is facilitated by its helicase activity. Using CRISPR-Cas9 genetic editing, we show that a heterozygous ( DDX49 +/- ) U2OS cell line is defective at cell migration, a phenotype supporting the association of DDX49 with cancer cell invasiveness. Measurement of RNAs in DDX49 +/- indicates that DDX49 is required to sustain levels of 5.8S rRNA., Competing Interests: We declare we have no competing interests., (© 2024 The Authors.)