How the Body Learns to Bypass Harsh Anti-Cancer Drugs

There are drugs (for example, alovudine) that are embedded in DNA during its copying and put an end to it: the chain breaks, the cell cannot divide normally - this is useful against viruses and cancer. But some cells manage to survive. A new paper published in Nucleic Acids Research explains how: the enzyme FEN1 helps "clear up the rubble", and the protein 53BP1, on the contrary, sometimes blocks everything with a tape and interferes with repair. The balance between them decides whether the cell will break or wriggle out.

Background

What kind of medicines and why are they needed? There are drugs that are built into DNA during its copying and put a "stopper" - the chain breaks, the cell cannot divide. This is useful against viruses and some tumors. An example is alovudine.

Where is the problem? Two troubles at once:

1. some normal cells suffer - side effects;
2. some cancer cells learn to survive such drugs - their effectiveness drops. Why this happens is not entirely clear.

How DNA is copied in general. Imagine laying a road: one stream goes in a continuous strip (the leading strand), the second in short pieces (the lagging strand). These pieces - "Okazaki fragments" - need to be carefully cut and glued together. This is done by the enzyme FEN1 - a kind of "edge trimmer" - without it, the seams are crooked and break.

Who raises the alarm. Protein 53BP1 is the "emergency service" of DNA: as soon as there is damage somewhere, it runs there, puts up warning "tapes" and turns on repair signals. In moderation, this is good, but if there are too many "tapes", the work stops - the road cannot be finished.

What was unclear before this study

• Why is it that the lagging chain (with its piecemeal assembly) is so vulnerable when exposed to “aborting” drugs?
• Can FEN1 help a cell “clean up” and move on, even if such a drug is included in the chain?
• And doesn't excess 53BP1 interfere with this process, turning normal perimeter security into a traffic jam?

Why did the authors take on the work?

Test a simple idea: the balance of FEN1 ↔ 53BP1 decides whether a cell will survive a blow to its DNA. If FEN1 manages to trim and glue fragments, and 53BP1 is not satisfied with the “road blockage,” the cell continues copying and survives; if not, the damage increases and the cell dies.

Why is this important next?

Having understood who and how saves the cell from “fragmentary” drugs, it is possible to:

• select combinations (enhance the effect where the tumor is too “cleverly repaired”);
• search for biomarkers (predict response and side effects based on FEN1 level/53BP1 behavior);
• make therapy more precise and safer.

A simple metaphor

Think of DNA copying as a paver laying out a new road.

• Alovudin is like a brick on a strip of asphalt: the roller runs over it and can’t go any further, the surface breaks.
• FEN1 is a team of clean-up workers: they cut off excess “flaps” and prepare the edges so that road workers can finally pave the asphalt evenly.
• 53BP1 - Emergency Service with barrier tape: sees a problem and puts up tape so that "nobody touches it". Sometimes this is useful, but if there is too much tape, the repair stops completely.

What scientists have shown

• When FEN1 was turned off, the cells became supersensitive to alovudine: lots of DNA damage, copying slowed down, survival dropped. Without a "clean-up crew," the debris can't be cleared.
• If 53BP1 is also removed from the same cells, the situation is partially normalized: the “tape” is removed, the repairmen can work again, and the cell tolerates the drug better.
• The main problem occurs in areas where DNA is copied in chunks (the so-called "Okazaki fragments"). There, fast trimming and "gluing" is especially important - the work of FEN1. And 53BP1, if there is too much of it, interferes with this process.

Translating from biology to everyday life: FEN1 helps to "clean up" and continue repairing the canvas, even if a "brick" (alovudine) is encountered. 53BP1 in reasonable limits - perimeter protection, but in excess it turns into a traffic jam.

Why do doctors and pharmacologists need to know this?

• Combinations of drugs. If the tumor has learned to tolerate "fragmentary" drugs, it may do so at the expense of FEN1. Then a double blow makes sense: to frag DNA + interfere with cleaning (target FEN1). This is still an idea for research, but already with a clear mechanism.
• Who will benefit and who won't. FEN1 levels and 53BP1 behavior can be considered biomarkers: they are better predictors of response and side effects.
• Safety: Understanding the FEN1 ↔ 53BP1 pathway could theoretically reduce toxicity to healthy cells by adjusting doses and schedules.

It is important not to overestimate

These were cell models, not clinical trials. We understand the mechanism, but we don’t yet know how best and safely to intervene in patients. Studies are needed in human tissue and with other drugs in the same class.

Conclusion

Drugs that break DNA are a powerful tool. But the outcome is decided by the cleanup after the accident. If the FEN1 "cleaner" copes and the "emergency tape" 53BP1 does not stifle the repair, the cell will survive the blow. If not, it will break. Having understood this dialogue between the two proteins, scientists get new ideas on how to enhance the anti-cancer effect and reduce the harm at the same time.