Power of cancer drugs may see boost by targeting newly ID’d pathway

Jan. 26, 2023
Researchers discover previously unknown way cells protect their genomes during replication.

Researchers at Washington University School of Medicine in St. Louis have identified a previously unknown signaling pathway cells use to protect their DNA while it is being copied. The findings, published January 24 in the journal Molecular Cell, suggest that targeting this pathway potentially could boost the potency of cancer therapeutics.

The process they discovered goes like this: When the DNA-duplicating machinery stalls, a protein called Exo1 that normally follows behind the machinery gets a little out of hand. Exo1’s job is to perform quality control by cutting out incorrectly copied pieces of DNA, but when the machinery stops moving forward, Exo1 starts snipping away haphazardly, cleaving off bits of DNA that then make their way out of the nucleus and into the main part of the cell. DNA is not found outside the nucleus under normal conditions, so its presence in the main part of the cell sets off an alarm. Upon encountering a fragment of DNA, a sensor molecule triggers a cascade of molecular events, including the release of the calcium ion from a cellular organelle known as the endoplasmic reticulum, which in turn shuts down Exo1, preventing it from dicing up the genome any further until the problem with the machinery can be fixed.

This newest study describes the discovery of DNA fragments as the warning signal that sets off the whole genome-protection response.

WUSTL release