Data from Loss of DNA Polymerase ζ Enhances Spontaneous Tumorigenesis

Abstract

<div>Abstract<p>Mammalian genomes encode at least 15 distinct DNA polymerases, functioning as specialists in DNA replication, DNA repair, recombination, or bypass of DNA damage. Although the DNA polymerase ζ (polζ) catalytic subunit REV3L is important in defense against genotoxins, little is known of its biological function. This is because REV3L is essential during embryogenesis, unlike other translesion DNA polymerases. Outstanding questions include whether any adult cells are viable in the absence of polζ and whether polζ status influences tumorigenesis. REV3L-deficient cells have properties that could influence the development of neoplasia in opposing ways: markedly reduced damage-induced point mutagenesis and extensive chromosome instability. To answer these questions, <i>Rev3L</i> was conditionally deleted from tissues of adult mice using <i>MMTV-Cre</i>. Loss of REV3L was tolerated in epithelial tissues but not in the hematopoietic lineage. Thymic lymphomas in <i>Tp53</i><sup>−/−</sup> <i>Rev3L</i> conditional mice occurred with decreased latency and higher incidence. The lymphomas were populated predominantly by <i>Rev3L</i>-null T cells, showing that loss of <i>Rev3L</i> can promote tumorigenesis. Remarkably, the tumors were frequently oligoclonal, consistent with accelerated genetic changes in the absence of <i>Rev3L</i>. Mammary tumors could also arise from <i>Rev3L</i>-deleted cells in both <i>Tp53</i><sup>+/+</sup> and <i>Tp53</i><sup>+/−</sup> backgrounds. Mammary tumors in <i>Tp53</i><sup>+/−</sup> mice deleting <i>Rev3L</i> formed months earlier than mammary tumors in <i>Tp53</i><sup>+/−</sup> control mice. Prominent preneoplastic changes in glandular tissue adjacent to these tumors occurred only in mice deleting <i>Rev3L</i> and were associated with increased tumor multiplicity. Polζ is the only specialized DNA polymerase yet identified that inhibits spontaneous tumor development. Cancer Res; 70(7); 2770–8</p></div>