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Loss of DNA polymerase zeta enhances spontaneous tumorigenesis
John P Wittschieben1, Vaishali Patil, Veronika Glushets
1Department of Pharmacology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA.
Abstract:
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 zeta (polzeta) 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 polzeta and whether polzeta 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, Rev3L was conditionally deleted from tissues of adult mice using MMTV-Cre. Loss of REV3L was tolerated in epithelial tissues but not in the hematopoietic lineage. Thymic lymphomas in Tp53(-/-) Rev3L conditional mice occurred with decreased latency and higher incidence. The lymphomas were populated predominantly by Rev3L-null T cells, showing that loss of Rev3L can promote tumorigenesis. Remarkably, the tumors were frequently oligoclonal, consistent with accelerated genetic changes in the absence of Rev3L. Mammary tumors could also arise from Rev3L-deleted cells in both Tp53(+/+) and Tp53(+/-) backgrounds. Mammary tumors in Tp53(+/-) mice deleting Rev3L formed months earlier than mammary tumors in Tp53(+/-) control mice. Prominent preneoplastic changes in glandular tissue adjacent to these tumors occurred only in mice deleting Rev3L and were associated with increased tumor multiplicity. Polzeta is the only specialized DNA polymerase yet identified that inhibits spontaneous tumor development.
Insights
DNA polymerase zeta (polzeta) loss in adult mice promotes cancer by increasing genetic instability, despite reducing DNA damage-induced mutations. This specialized DNA polymerase inhibits spontaneous tumor development.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Mammalian genomes contain numerous DNA polymerases with specialized roles in DNA replication, repair, and damage tolerance.
- DNA polymerase zeta (polzeta), encoded by REV3L, is crucial for genotoxin defense but its broader biological function remains unclear due to its essential role in embryogenesis.
- Outstanding questions concern the viability of adult cells lacking polzeta and its influence on cancer development.
Purpose of the Study:
- To investigate the biological function of polzeta (REV3L) in adult mammalian tissues.
- To determine if polzeta deficiency impacts tumorigenesis and cancer progression.
- To elucidate the opposing effects of REV3L deficiency on mutagenesis and chromosome instability in the context of neoplasia.
Main Methods:
- Conditional deletion of Rev3L in adult mice using the MMTV-Cre system.
- Analysis of Rev3L loss tolerance in epithelial versus hematopoietic lineages.
- Assessment of thymic lymphoma and mammary tumor development in Rev3L-deficient mice, including Tp53 mutant backgrounds.
- Evaluation of tumor latency, incidence, clonality, and preneoplastic changes.
Main Results:
- Rev3L deletion was tolerated in epithelial tissues but not the hematopoietic lineage.
- Loss of Rev3L accelerated thymic lymphoma development in Tp53(-/-) mice, with tumors predominantly composed of Rev3L-null T cells.
- Mammary tumors developed earlier and with increased multiplicity in Rev3L-deleted mice, exhibiting preneoplastic changes.
- Tumors in Rev3L-deficient mice showed oligoclonality, indicating accelerated genetic alterations.
Conclusions:
- Polzeta (REV3L) is essential in the hematopoietic lineage and its loss can promote tumorigenesis.
- REV3L deficiency leads to increased chromosome instability and accelerated genetic changes, contributing to tumor formation.
- Polzeta is identified as the sole specialized DNA polymerase that actively inhibits spontaneous tumor development.
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