POLD3 Is Haploinsufficient for DNA Replication in Mice

Mol Cell. 2016 Sep 1;63(5):877-83. doi: 10.1016/j.molcel.2016.07.007. Epub 2016 Aug 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Brain / growth & development
  • Brain / metabolism
  • Brain / pathology
  • Cell Death
  • Checkpoint Kinase 1 / genetics
  • Checkpoint Kinase 1 / metabolism
  • DNA Damage
  • DNA Polymerase III / deficiency*
  • DNA Polymerase III / genetics
  • DNA Replication*
  • Gene Expression Regulation, Developmental
  • Haploinsufficiency*
  • Histones / genetics
  • Histones / metabolism
  • Homozygote
  • Hydrocephalus / genetics*
  • Hydrocephalus / metabolism
  • Hydrocephalus / mortality
  • Hydrocephalus / pathology
  • Longevity / genetics*
  • Lung / growth & development
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Survival Analysis

Substances

  • H2AX protein, mouse
  • Histones
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • DNA Polymerase III
  • POLD3 protein, mouse