Source: NIH
Source: NIH

Scientists at the National University of Ireland Galway have recently shown that the TP53 gene has even greater anti-cancer activity than previously suspected. The new study—“A role for the p53 tumour suppressor in regulating the balance between homologous recombination and non-homologous end joining”—published recently in Open Biology, provides new insight into the function of a gene long known for its importance in the suppression of cancer.

“TP53 is one of the most potent genes in the human genome at preventing cancer and hence is termed a tumor suppressor gene,” explained senior study author Noel Lowndes, Ph.D., head of the Centre for Chromosome Biology at NUI Galway and a Science Foundation Ireland principal investigator. “The importance of TP53 as a tumor suppressor is best illustrated by its mutation in at least half of all human cancers.”

The p53 transcription factor is a critical protein involved in maintaining genomic integrity. In previous studies, investigators have shown that TP53 functions in processes that prevent cancer cells from multiplying in the body by either triggering their destruction or preventing cell division. Together, these processes are recognized as potent anti-cancer mechanisms. 

“In our recent work we add a new role to the expanding list of anti-cancer mechanisms controlled by TP53,” Dr. Lowndes noted. “We show that TP53 directly regulates the repair of broken DNA. Broken DNA is the most dangerous type of DNA damage as it can result in cell death or loss of genetic information in those cells that survive the break.”

Specifically, the researchers found that p53 had a direct role in modifying DNA repair mechanisms.

“Here, we provide evidence supporting a novel role for p53 in the regulation of DNA double-strand break (DSB) repair pathway choice,” the authors wrote. “53BP1, another tumor suppressor, was initially identified as p53 Binding Protein 1 and has been shown to inhibit DNA end resection, thereby stimulating non-homologous end joining (NHEJ). Yet another tumor suppressor, BRCA1, reciprocally promotes end resection and homologous recombination (HR).”

“There are two major competing biochemical pathways for repairing broken DNA,” Dr. Lowndes added. “One simply re-joins the two ends of the broken chromosome. The other uses a nearby intact DNA molecule of the same sequence as a template to repair the broken chromosome.”

The research team is optimistic that their new insights will have an impact on the diagnosis of cancer and improve therapeutic interventions.

“Our work demonstrates that TP53 directly influences the regulation of these two pathways. Thus, loss of TP53 during cancer development will drive the evolution of cancer cells towards ever more aggressive cancer types,” Dr. Lowndes concluded.

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