Thursday, January 15, 2009

Protein's Essential Role In Repairing Damaged Cells Revealed

University of Michigan researchers have discovered that a key protein in cells plays a critical role in not one, but two processes affecting the development of cancer.

"Most proteins involved in responding to DNA damage that can cause cancer either help detect the damage and warn the rest of the cell, or help repair the damage," says David O. Ferguson, M.D., Ph.D., the study's lead author. Ferguson is an assistant professor of pathology at the U-M Medical School and a member of U-M's Comprehensive Cancer Center.

Prior research has shown that the protein, Mre11, functioned as a "gatekeeper" to signal injury to the cell and prevent damaged cells from proliferating. Now, Ferguson and colleagues have discovered that in mammals, a function of the Mre11 protein also serves as a "caretaker," by repairing DNA.

Their findings, published in the journal Cell, could have important implications for cancer treatment by someday allowing oncologists to predict a tumor's sensitivity to radiation and other therapies, making it more vulnerable to treatment.

Under normal circumstances, the body's cells grow, divide and eventually die. When something damages a healthy cell's DNA -- such as radiation or exposure to a toxin -- a multiprotein complex steps in to repair the breakage and activate other fundamental cellular processes.

The MRN complex, comprised of the Mre11, Rad50 and NBS1 proteins, senses DNA damage, known as double-strand breaks, within the cell. The complex then transmits that information to an enzyme called the ATM (ataxia-telangiectasia mutated) checkpoint kinase.

The ATM kinase controls the cell's response to double-strand breaks, and slows cell growth to give the cell opportunities to repair them, says Ferguson.

When the MRN complex doesn't work properly, inherited human neurological diseases, such as ataxia-telangiectasia-like syndrome and Nijmegen breakage syndrome, result. Both feature MRN mutations and significantly predispose a person to immunodeficiency and cancer.

What Ferguson and colleagues discovered is that Mre11 not only senses and communicates damage, it also repairs DNA double-strand breaks by acting as a nuclease, an enzyme that modifies and processes the broken DNA ends.

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