Every time a cell divides, it has to copy billions of pieces of DNA. It is an incredibly complicated process, and mistakes or damage are inevitable. Healthy cells have several ways to fix those problems before they become dangerous.
Cancer cells do, too.
In a new study published in Nucleic Acids Research, researchers from UT San Antonio, including investigators affiliated with the Greehey Children’s Cancer Research Institute, uncovered an important backup system that some cancer cells depend on to repair damaged DNA and survive.
The discovery could eventually give researchers another way to attack cancers that already have weaknesses in their normal DNA-repair machinery.
When Cancer Loses Its Best Repair Tool
One of the body’s major DNA-repair genes is BRCA1. Think of BRCA1 as part of a highly skilled repair crew. When DNA breaks or runs into trouble while being copied, BRCA1 helps the cell make an accurate repair.
But some cancer cells lack a working BRCA1 gene.
That sounds like it should be bad news for the cancer cell—and it is. But cancer cells are remarkably good at adapting. Instead of relying on their preferred repair system, BRCA1-deficient cancer cells can switch to alternative methods that are less precise but may be good enough to keep the cell alive.
The new study examined one of those backup systems.
Researchers discovered that three proteins—PCNA, RECQL5 and RPRD1B—help assemble a repair team at locations where DNA copying has stalled or become damaged.
The names are complicated. Their job is easier to understand.
Imagine DNA being copied along an assembly line. When that assembly line suddenly stops because the DNA is damaged, the cancer cell needs to get a repair crew to the problem quickly.
The researchers found that PCNA helps recruit RECQL5, which in turn brings in RPRD1B. RPRD1B then helps gather additional proteins needed to repair the damaged DNA and restart the process.
Take Away the Backup—and the Cancer Cell Struggles
The most interesting finding came when researchers interfered with RPRD1B.
Without enough RPRD1B, BRCA1-deficient cancer cells struggled to repair their DNA. Damage accumulated, chromosomes developed serious problems during cell division, and the cancer cells were much more likely to die.
Cells with functioning BRCA1 were considerably less affected.
That difference is important.
Cancer researchers are constantly looking for biological weaknesses that cancer cells depend on more heavily than healthy cells. If a future treatment could selectively disrupt one of those dependencies, it could potentially make it harder for the cancer cell to survive while limiting effects on normal cells.
The study suggests that this newly described DNA-repair pathway may represent one such vulnerability in BRCA1-deficient cancers. The researchers also note that targeting this pathway could someday offer another strategy for cancers that have become resistant to existing DNA-repair drugs such as PARP inhibitors. Much more research would be required before that possibility becomes a treatment.
Why This Matters to Childhood Cancer Research
This study was not conducted specifically as a childhood cancer treatment study, but the biology it explores has important implications for pediatric cancer research.
Problems with DNA repair are not limited to adult cancers. Large genomic studies of childhood tumors have found evidence of defects in the same broad DNA-repair process—called homologous recombination—in pediatric cancers including osteosarcoma, neuroblastoma, Wilms tumor and B-cell acute lymphoblastic leukemia.
Understanding how cancer cells compensate when their normal repair systems fail gives researchers new clues about how those cells survive—and where they may be vulnerable.
That is one of the foundations of precision cancer research: instead of attacking every cancer cell the same way, scientists look for the specific biological machinery a tumor depends on and ways to disrupt it.
For childhood cancers, where researchers are continually working toward treatments that are both more effective and less damaging to developing bodies, identifying these cancer-specific vulnerabilities is particularly important.
Discovery Starts With Understanding
This research does not mean a new treatment is ready for patients. It represents an earlier—and essential—part of the process.
By uncovering a previously unknown chain of events that helps certain cancer cells repair damaged DNA, researchers have identified another piece of cancer’s survival strategy.
And once scientists understand how a cancer cell keeps itself alive, they can begin asking the next question:
What happens if we take that survival mechanism away?