Adaptive use of error‐prone DNA polymerases provides flexibility in genome replication during tumorigenesis

• Published in: Cancer science Vol. 115; no. 7; pp. 2125 - 2137
• Main Authors: Bainbridge, Lewis J., Daigaku, Yasukazu
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2024; John Wiley and Sons Inc
• Subjects: Accuracy; Animals; Antigens; Breast cancer; Cancer; Carcinogenesis - genetics; Cell cycle; Cell survival; Chemoresistance; DNA biosynthesis; DNA damage; DNA polymerase; DNA repair; DNA Repair - genetics; DNA Replication; DNA-directed DNA polymerase; DNA-Directed DNA Polymerase - genetics; DNA-Directed DNA Polymerase - metabolism; Flexibility; Genomes; Humans; Mitochondrial DNA; Mutagenesis; Mutation; Neoplasms - genetics; Neoplasms - pathology; PCNA ubiquitylation; Proliferating Cell Nuclear Antigen - genetics; Proliferating Cell Nuclear Antigen - metabolism; Replication; replication stress; Review; Tumorigenesis; Ubiquitin; Ubiquitination; DNA replication; replication stress; DNA polymerase; mutagenesis; PCNA ubiquitylation
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.16188

Human cells possess many different polymerase enzymes, which collaborate in conducting DNA replication and genome maintenance to ensure faithful duplication of genetic material. Each polymerase performs a specialized role, together providing a balance of accuracy and flexibility to the replication process. Perturbed replication increases the requirement for flexibility to ensure duplication of the entire genome. Flexibility is provided via the use of error‐prone polymerases, which maintain the progression of challenged DNA replication at the expense of mutagenesis, an enabling characteristic of cancer. This review describes our recent understanding of mechanisms that alter the usage of polymerases during tumorigenesis and examines the implications of this for cell survival and tumor progression. Although expression levels of polymerases are often misregulated in cancers, this does not necessarily alter polymerase usage since an additional regulatory step may govern the use of these enzymes. We therefore also examine how the regulatory mechanisms of DNA polymerases, such as Rad18‐mediated PCNA ubiquitylation, may impact the functionalization of error‐prone polymerases to tolerate oncogene‐induced replication stress. Crucially, it is becoming increasingly evident that cancer cells utilize error‐prone polymerases to sustain ongoing replication in response to oncogenic mutations which inactivate key DNA replication and repair pathways, such as BRCA deficiency. This accelerates mutagenesis and confers chemoresistance, but also presents a dependency that can potentially be exploited by therapeutics. Perturbed replication increases the requirement for flexibility to ensure duplication of the entire genome. Flexibility is provided via the use of error‐prone polymerases, which maintain the progression of challenged DNA replication but increase mutagenesis, an enabling characteristic of cancer. This review describes our recent understanding of mechanisms that alter the usage of polymerases during tumorigenesis and examines the implications of this for cell survival and tumor progression.