New gene-editing system enables large-scale studies of gene function.
CAMBRIDGE, Mass.--A key gene that prevents human cells from becoming cancerous has two very helpful relatives, Massachusetts Institute of Technology researchers report in the April 4 issue of Nature.
This work represents a step toward better understanding how cells choose to commit suicide following damage to their DNA, says MIT postdoctoral fellow and author Elsa R. Flores. Other authors are Tyler Jacks, professor of biology at MIT, director of MIT's Center for Cancer Research and a Howard Hughes Medical Investigator; Kenneth Y. Tsai of the Harvard-MIT Division of Health Sciences and Technology; and Annie Yang and Frank McKeon of Harvard Medical School's department of cellular biology.
"The process of DNA damage-induced cell death is key to both tumor development and the response of cancer cells to therapy," Jacks said. "This new work reveals a layer of regulation of this process that is very interesting and very unexpected."
The tumor suppressor gene p53 has long been known to be a key player in cells' ability to respond to DNA damage. The malfunction of p53 is known to spur the progression of certain human cancers.
Two p53 family members--genes p63 and p73--seem to modulate the activity of p53. Important players in this critical cellular process, p63 and p73 may protect organisms from developing tumors.
FIXING THE DAMAGE
Healthy cells' defense against outside onslaughts to their genetic material is the DNA damage response pathway. This pathway leads to apoptosis, also known as cellular suicide. When threatened with carcinogens, this is the cell's last-ditch effort to prevent damage to the organism.
Without p53, cells are unable to undergo apoptosis.
A normal cell that has become cancerous also does not undergo apoptosis. Cancer cells proliferate out of control, somehow subverting healthy cells' ability to die off when necessary.
In addition, the effectiveness of chemotherapy in fighting tumors is thought to be determined in part by the ability of the targeted cells to engage in cellular suicide, Flores said.
MORE KEY GENES
About five years ago, researchers identified two p53 family members, p63 and p73, which are structurally similar to p53.
In this study, by using cells and tissues lacking both the p63 and p73 genes, the authors demonstrated that p63 and p73 also are important players in the cell's ability to undergo programmed cell death in response to DNA damage, Flores said.
"We found that cells and tissues derived from mice lacking both p63 and p73 are unable to undergo apoptosis when challenged with chemotherapeutic agents or radiation," Flores said. "Mechanistically, this appears to be due to the fact that some of the genes necessary for cellular suicide that are normally activated by p53 in response to DNA damage are not activated in cells and tissues lacking p63 and p73.
"We also showed that p53 itself could not be found at the promoters of these apoptotic genes in cells lacking both p63 and p73, and that p63 can be found at these promoters even in the absence of p53. This indicates that p63 and p73 play a previously undetermined role in modulating the activity of p53," she said.
This work is supported by the National Institutes of Health, the Howard Hughes Medical Institute and the Leukemia and Lymphoma Society of America.