Cell Gatekeeper and Repair Protein Mutated in Certain Cancers

January 7, 2009
Julia Ernst, MS

Researchers have discovered a protein in mammalian cells that plays a large role in two aspects of cancer development.

Researchers at the University of Michigan have discovered a protein in mammalian cells that plays a large role in two aspects of cancer development. The MRN complex—made of the Mre11, Rad50 and NBS1 proteins—senses DNA damage — double-strand breaks — inside a cell.

Mre11, isolated and the focal point of research, is already known for its “gatekeeper” role, signaling injury and preventing proliferation of the damaged cell. David O. Ferguson, MD, PhD, the study's lead author, and colleagues at the University of Michigan discovered that it also functions as a caretaker of the cell by repairing damaged DNA.

Researchers worked with two mouse models to examine the role of Mre11 in the MRN complex—one in which Mre11 was destroyed entirely, and another in which only a single amino acid was changed. In both cases, the consequences were equally bad, which came as a surprise to the researchers. Extracting a single amino acid from Mre11 that is responsible for nuclease activity led to the development of growth defects, chromosomal abnormalities, and sensitivity to DNA-damaging agents in the mice. This led researchers to conclude that the repair activity of Mre11 is crucial in both MRN function and stability of the genetic material of the organism.

According to the University of Michigan’s website release, a preview article in Cell called the research "virtuoso cell engineering.” Researchers at the university add that the findings could be helpful in identifying mutations associated with numerous cancers.

"What's emerging in the literature from large-scale screening studies of human tumors is that Mre11 may be frequently mutated in certain cancers," Ferguson said. "This may have implications for diagnoses because tumors associated with different mutations may have different prognoses and respond to different therapies." Ferguson added that this discovery could also allow oncologists to more directly pinpoint what treatments may work better for certain cancers.

“The fact that we have now separated the functions of DNA repair from the checkpoint functions means we may have identified a target that can sensitize tumors to radiation and chemotherapeutic agents used in treating cancer,” he said.

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