(Press-News.org)
Tokyo, Japan – Researchers from Tokyo Metropolitan University have discovered a new pathway by which cells counteract the action of alovudine, an important antiviral and anticancer drug. The protein flap endonuclease-1 (Fen1) was found to improve cell tolerance by counteracting the toxic accumulation of another protein, 53BP1. A renewed spotlight on the underappreciated role of Fen1 promises not only new cancer treatments, but a way to gauge the efficacy of existing treatments.
Chain-terminating nucleoside analogs (CTNAs) are molecules which closely resemble nucleosides, the building blocks of DNA. They have been used as antiviral and cancer treatments since the 1980s due to their ability to bind to DNA as they are replicated. Since replication rates are abnormally high in infected or cancerous cells, these cells take up more of the drug, suppressing their growth. However, there is much that we don’t know about how healthy cells resist the action of CTNA toxicity, limiting how we put them to good use. For example, alovudine, a CTNA containing fluorine, was envisioned as an HIV treatment, but clinical trials were stopped at phase II due to their toxicity.
A team led by Professor Kouji Hirota of Tokyo Metropolitan University have been looking at the pathways by which healthy cells resist the action of CTNAs. In previous work on alovudine, they had discovered the important role played by breast cancer type I susceptibility protein (BRCA1), a key player in DNA repair. Now, they have turned to the underappreciated role played by flap endonuclease-1 (Fen1), another DNA repair protein responsible for cutting off short, single-stranded DNA sections hanging off a replicating section of DNA known as an Okazaki fragment.
In their experiments with genetically modified chicken DT40 cells, a common model system, the team discovered that suppression of Fen1 made cells extremely susceptible to alovudine toxicity, with replication speeds significantly reduced. Strikingly, they discovered that the further loss of a gene encoding for an entirely different protein led to recovery of alovudine tolerance. Known as 53BP1, this protein is known to collect at nicks in double-stranded DNA. This suggests a mechanism where a lack of Fen1 firstly leads to long overhangs, or “flaps”, being left on replicating DNA. When alovudine is incorporated, the 53BP1 accumulates around the flap, impeding other available mechanisms for cleaving off the overhang, effectively terminating DNA replication.
The team also carried out experiments extending their previous work on BRCA1. At the time, they found that homologous recombination (HR), a key DNA repair pathway involving BRCA1, was significant in their alovudine tolerance. While having either Fen1 or HR suppressed led to lowered resistance, having both led to significantly more suppression. This suggests that the newly found significance of Fen1 is independent of the previous role identified for BRCA1.
A deeper understanding of CTNA tolerance might yield not only promising new treatments but also effect biomarking of cancerous cells which often have a Fen1 deficiency, and a way to ascertain how effective drugs like alovudine might be. The team aims to move to studies in human cells, and work on how such treatments might be applied to different cancerous tissues, such as solid tumors.
This work was supported by JSPS KAKENHI Grants-in-Aid (JP25K02256, JP21K19235, JP20H04337, JP22K15040, and 19KK0210), Tokyo Metropolitan Government Advanced Research Grant Number (R3-[2]), the Takeda Science Foundation, and the Uehara Memorial Foundation.
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