For almost 30 years, medical researchers have been aware of the importance of the p53 gene in preventing cancer. More than half the cancers in the world involve mutations in this gene, but how it performs its role has been largely a mystery. So the identification of the role of other genes that work in combination with p53 could transform the battle against cancer.
The latest edition of Nature Medicine has three papers devoted to p53. One of these papers has grabbed the headlines for revealing that the exceptionally powerful gene-editing technology CRISPR can kill embryonic stem cells. However, Dr Ana Janic of the Walter and Eliza Hall Institute of Medical Research told IFLScience the paper on which she is first author is unconnected to that one, but could also have immensely important consequences.
Janic and her co-authors studied the way p53 prevents B-cell lymphomas, a type of blood cancer. She found that a number of other genes, principally MLH1, are crucial, repairing damaged DNA within cells that could become tumors.
“It has long been assumed that p53 suppresses tumor development through induction of apoptosis [cell death],” the paper reports. Although this is part of the story, the study found p53 works in multiple ways, and killing cells that might become cancerous is only one of them.
Janic told IFLScience that “p53 is a master gene”, regulating the behavior of a host of other genes. One thing it does is combine with genes that repair defects in DNA, fixing cells so that killing them is unnecessary.
In particular, the authors demonstrated that when MLH1 repair genes are lost or malfunctioning, p53 ceases to function properly, and lymphomas develop. On the other hand, when they forced the expression of MLH1 where p53 was absent, tumor suppression was still achieved. In other words, p53 works not only by killing the most dangerous cells, but by directing repair genes to fix those cells that are not beyond saving.
“When MLH1 was put back into the equation, tumour development was significantly stalled,” co-author Dr Marco Herold said in a statement. “This led us to explore other DNA repair genes and it has become clear just how important the whole DNA repair machinery is to p53’s ability to prevent cancer development.”
Although the research was on only one type of cancer, p53 mutations are present in 70 percent of colon and pancreatic cancers, and common in many other organs’ tumors. Janic anticipates in these cases p53 will also often be acting through repair genes.
Long term the findings offer additional targets for therapies. More immediately, they may help doctors assess which existing treatments will best suit patients since in cases where MLH1 is malfunctioning, chemotherapy can make cancers more aggressive, rather than control them.