Credit: Beth A. Sullivan
New research suggests DNA ligase 3 is crucial for the evolutionary processes that drive cancer.
“We have identified a gene that, as cells age, seems to regulate whether the cells become cancerous or not,” said Eric A. Hendrickson, PhD, of the University of Minnesota in Minneapolis.
“This gene has never been identified before in this role, so this makes it a potentially very important therapeutic target.”
Dr Hendrickson and his colleagues recounted this discovery in Cell Reports.
The researchers noted that short, dysfunctional telomeres can fuse, thereby generating dicentric chromosomes and initiating breakage-fusion-bridge cycles. The cells that manage to escape the subsequent crisis have genomic rearrangements that drive clonal evolution and malignant progression.
The team wanted to determine exactly what allows these malignant cells to escape telomere-driven crisis and avoid death.
To find out, the group disabled certain genes in human cells and then studied the impact this had on telomere fusion.
They found that cells escaped death when ligase 3 was active but not when its action, which appears to promote fusion within like chromosomes rather than between different chromosomes, was inhibited.
“Telomere dysfunction has been identified in many human cancers,” said study author Duncan Baird, PhD, of Cardiff University in the UK.
“And, as we have shown previously, short telomeres can predict the outcome of patients with [chronic lymphocytic leukemia] and probably many other tumor types. Thus, the discovery that ligase 3 is required for this process is fundamentally important.”
This research was made possible by a chance meeting between Dr Baird and Dr Hendrickson at an international conference. The pair discovered they were both looking at the role of ligase 3 in cancer and decided to collaborate.
“The collaboration paid off, as we were able to uncover something that neither one of us could have done on our own,” Dr Hendrickson said.
Additional studies are already underway. The researchers are investigating the discovery that the reliance on ligase 3 appears to be dependent upon the activity of another key DNA repair gene, p53.
“Since p53 is the most commonly mutated gene in human cancer, it now behooves us to discover how these two genes are interacting and to see if we can’t use that information to develop synergistic treatment modalities,” Dr Hendrickson concluded.
