Polε instability drives replication stress, abnormal development, and tumorigenesis
journal contributionposted on 2020-07-01, 11:42 authored by Roberto Bellelli, Valerie Borel, Clare Logan, Jennifer Svendsen, Danielle Cox, Emma Nye, Kay Metcalfe, Susan M O’Connell, Gordon Stamp, Helen R Flynn, Ambrosius P Snijders, François Lassailly, Andrew Jackson, Simon J Boulton
DNA polymerase ε (POLE) is a four-subunit complex and the major leading strand polymerase in eukaryotes. Budding yeast orthologs of POLE3 and POLE4 promote Polε processivity in vitro but are dispensable for viability in vivo. Here, we report that POLE4 deficiency in mice destabilizes the entire Polε complex, leading to embryonic lethality in inbred strains and extensive developmental abnormalities, leukopenia, and tumor predisposition in outbred strains. Comparable phenotypes of growth retardation and immunodeficiency are also observed in human patients harboring destabilizing mutations in POLE1. In both Pole4-/- mouse and POLE1 mutant human cells, Polε hypomorphy is associated with replication stress and p53 activation, which we attribute to inefficient replication origin firing. Strikingly, removing p53 is sufficient to rescue embryonic lethality and all developmental abnormalities in Pole4 null mice. However, Pole4-/-p53+/- mice exhibit accelerated tumorigenesis, revealing an important role for controlled CMG and origin activation in normal development and tumor prevention.
DNA polymerase εDNA replicationPOLE1/2 mutationsgenome stabilityp53tumorigenesisAnimalsCarcinogenesisCells, CulturedDNA Polymerase IIDNA ReplicationDevelopmental DisabilitiesEmbryo, MammalianFemaleGrowth DisordersHumansInfant, NewbornLeukopeniaMaleMiceMice, Inbred C57BLMice, KnockoutMutationTumor Suppressor Protein p53Boulton FC001048HPPRTBRF-ack06 Biological Sciences11 Medical and Health SciencesDevelopmental Biology