title: POLD3 Is Haploinsufficient for DNA Replication in Mice.
abstract: The Pold3 gene encodes a subunit of the Polδ DNA polymerase complex. Pold3 orthologs are not essential in Saccharomyces cerevisiae or chicken DT40 cells, but the Schizosaccharomyces pombe ortholog is essential. POLD3 also has a specialized role in the repair of broken replication forks, suggesting that POLD3 activity could be particularly relevant for cancer cells enduring high levels of DNA replication stress. We report here that POLD3 is essential for mouse development and is also required for viability in adult animals. Strikingly, even Pold3(+/-) mice were born at sub-Mendelian ratios, and, of those born, some presented hydrocephaly and had a reduced lifespan. In cells, POLD3 deficiency led to replication stress and cell death, which were aggravated by the expression of activated oncogenes. Finally, we show that Pold3 deletion destabilizes all members of the Polδ complex, explaining its major role in DNA replication and the severe impact of its deficiency.
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre, Madrid 28029, Spain. Electronic address: mmurga@cnio.es.
authors.forename: Matilde
authors.initials: M
authors.lastname: Murga
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre, Madrid 28029, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Lecona
authors.affiliation: Department of Molecular Biology, University of Geneva, Geneva 1211, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Kamileri
authors.affiliation: DNA Replication Group, Spanish National Cancer Research Centre, Madrid 28029, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Díaz
authors.affiliation: Department of Molecular Biology, University of Geneva, Geneva 1211, Switzerland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lugli
authors.affiliation: Department of Molecular Biology, University of Geneva, Geneva 1211, Switzerland.
authors.forename: Sotirios K
authors.initials: SK
authors.lastname: Sotiriou
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre, Madrid 28029, Spain.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Anton
authors.affiliation: DNA Replication Group, Spanish National Cancer Research Centre, Madrid 28029, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Méndez
authors.affiliation: Department of Molecular Biology, University of Geneva, Geneva 1211, Switzerland.
authors.forename: Thanos D
authors.initials: TD
authors.lastname: Halazonetis
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre, Madrid 28029, Spain; Science for Life Laboratories, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 171 77, Sweden. Electronic address: ofernandez@cnio.es.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D000071877:Checkpoint Kinase 1 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004258:DNA Polymerase III / Q000172:deficiency* / Q000235:genetics; D004261:DNA Replication; D018507:Gene Expression Regulation, Developmental; D057895:Haploinsufficiency; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D006849:Hydrocephalus / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008136:Longevity / Q000235:genetics*; D008168:Lung / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D016019:Survival Analysis
chemical_list: D000071877:Checkpoint Kinase 1; D004258:DNA Polymerase III; D006657:Histones; C000605869:Chek1 protein, mouse; C000622315:POLD3 protein, mouse; C475961:gamma-H2AX protein, mouse