A team of scientists from Tokyo Metropolitan University has uncovered a new way that cells can protect themselves from the toxic effects of certain powerful drugs used to treat cancer and viral infections.
The study, published in Nucleic Acids Research, focuses on a lesser-known DNA repair protein called flap endonuclease-1 (Fen1) and its role in helping cells tolerate the drug alovudine.
Alovudine belongs to a group of compounds called chain-terminating nucleoside analogs (CTNAs).
These drugs mimic the building blocks of DNA and are incorporated into DNA strands during replication.
Because cancer cells and virus-infected cells replicate their DNA much faster than healthy cells, they absorb more of the drug, which stops their growth. CTNAs have been used since the 1980s against viruses like HIV and certain cancers.
However, CTNAs can also damage healthy cells, limiting their use. Alovudine, for example, showed promise as an HIV treatment but was abandoned after early clinical trials due to toxicity.
Until now, scientists did not fully understand how normal cells defend themselves against these drugs.
Professor Kouji Hirota’s team had previously shown that BRCA1, a well-known DNA repair protein, helps cells resist alovudine.
In their new research, they turned to Fen1, another DNA repair protein that works by cutting away short, single-stranded pieces of DNA—known as “flaps”—that appear during replication.
Using genetically modified chicken DT40 cells, the researchers found that removing Fen1 made cells extremely vulnerable to alovudine.
DNA replication slowed significantly, and cell survival dropped. Surprisingly, when they also removed another protein, 53BP1, the cells regained their ability to tolerate the drug.
This finding suggests that without Fen1, long flaps of DNA are left behind during replication.
When alovudine is incorporated into these flaps, 53BP1 collects at the damaged sites, blocking other repair pathways and halting DNA replication. Without 53BP1, these alternative pathways can operate, allowing the cell to recover.
The team also investigated how Fen1’s role relates to BRCA1 and its involvement in homologous recombination (HR), a key DNA repair pathway. They found that removing either Fen1 or HR reduced resistance to alovudine, but removing both caused an even greater loss of tolerance. This means Fen1 helps protect cells through a pathway independent of BRCA1 and HR.
Understanding how cells resist CTNAs like alovudine could lead to new cancer treatments and tools for predicting how well certain drugs will work. Since many cancer cells have low Fen1 activity, targeting this vulnerability might make CTNA drugs more effective.
The next step for the researchers is to test their findings in human cells and explore how this knowledge could be applied to different cancer types, including solid tumors.
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Source:KSR.
