Chromosomal mutational signatures of DNA damaging agents at single cell resolution
The chromosomal-scale mutational spectrum of small molecules that interact with DNA has been hard to study at scale, as mutational events are distributed in location and occur in parallel in different cells. Here, we present a framework that pairs phylogenetic ancestry reconstruction with mutational signature decomposition to characterise recent, cell-private copy number alteration (CNA)…
Scientists have developed a new method for studying the genetic mutations caused by tiny molecules that interact with DNA. This method allows researchers to examine these mutations at a single-cell level, which is crucial as the mutations are often spread out in location and occur simultaneously in different cells. By applying this framework, researchers have been able to analyze the genetic changes in cells exposed to chemotherapeutic drugs that induce double-strand breaks in DNA.
The findings reveal that platinum salts, G-quadruplex stabilizers, and topoisomerase II inhibitors, despite their distinct mechanisms, share a similar genetic signature. This signature is characterized by telomere-bounded copy-number gains and losses. This pattern was observed in various genetic backgrounds and in living organisms treated with these drugs. Additionally, the study found a high rate of telomere-bounded mutational foreground in cells deficient in BRCA1, a gene associated with breast and ovarian cancer.
The researchers discovered that the genetic signature of the mutations is dependent on the dose of the drug used. Furthermore, they observed that the effects of exposure to certain drugs, such as cisplatin and a molecule that stabilizes G-quadruplex structures (CX5461), can persist for up to three weeks after the drug is withdrawn. This suggests that the residual effects of drug exposure may last longer than previously thought.
The study also extends to patient-derived xenograft (PDX) models, where serial drug treatment was applied. The results indicate that the exposure to telomere-bounded CNA (copy number alteration) signature is associated with the tumor's response to the drug. This association is particularly notable when acquired resistance emerges, as it is linked to a loss of mutational activity in the genome.
In summary, this new framework, when applied to single-cell whole-genome sequencing (scWGS), provides insights into the contemporaneous chromosomal mutation patterns induced by small molecules in human tissues.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
