Altered DNA Polymerase ι Expression in Breast Cancer Cells Leads to a Reduction in DNA Replication Fidelity and a Higher Rate of Mutagenesis

Abstract

The recently discovered human enzyme DNA polymerase (pol ) has been shown to have an exceptionally high error rate on artificial DNA templates. Although there is a considerable body of in vitro evidence for a role for pol in DNA lesion bypass, there is no in vivo evidence to confirm this action. We report here that pol expression is elevated in breast cancer cells and correlates with a significant decrease in DNA replication fidelity. We also demonstrate that UV treatment of breast cancer cells additionally increases pol expression with a peak occurring between 30 min and 2 h after cellular insult. This implies that the change in pol expression is an early event after UV-mediated DNA damage. That pol may play a role in the higher mutation frequencies observed in breast cancer cells was suggested when a reduction in mutation frequency was found after pol was immunodepleted from nuclear extracts of the cells. Analysis of the UV-induced mutation spectra revealed that >90% were point mutations. The analysis also demonstrated a decreased C3 T nucleotide transition and an increased C3 A transversion rate. Overall, our data strongly suggest that pol may be involved in the generation of both increased spontaneous and translesion mutations during DNA replication in breast cancer cells, thereby contributing to the accumulation of genetic damage.

Overexpression of DNA polymerase iota (Polι) in esophageal squamous cell carcinoma

“…Polymerase ι, the product of the RAD30B gene, has been documented to be upregulated in several cancers, (25,26) but its expression pattern has not been reported in esophageal cancer tissues. Polymerase ι could be the most error-generating DNA polymerase, commonly misincorporating G opposite a template T in an undamaged DNA strand.…”

Stress responses and genetic variation in bacteria

“…Alternatively, a transient mutator state could result from the induction of an error-prone polymerase as part of a stress response. Recently both breast and lung cancer cells have been shown to have elevated levels of an error-prone polymerase [76,77]; in the breast cancer cells, Pol ι was further induced by exposure to UV-light [77]. Further research into the mechanisms that regulate the activity and the error-prone polymerases will shed light on the role that these enzymes play in the development of cancer and other genetic diseases.…”

A cancer-associated PCNA expressed in breast cancer has implications as a potential biomarker

“…We determined that the cancer-associated isoform of PCNA (caPCNA) does not arise because of a genetic mutation but, more likely, as a result of posttranslational modification. In addition, we have shown that breast cancer cells carry out an error-prone DNA synthesis both in vitro and in vivo (16,17). Therefore, additional studies to structurally and functionally understand the role that caPCNA plays in breast cancer cells are warranted.…”