Protein's essential role in repairing damaged cells revealedJanuary 07, 2009ANN ARBOR, Mich. - 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. Research details The researchers generated mouse models to examine the exact role of Mre11 in the MRN complex. They engineered two mouse strains, one in which Mre11 was disabled completely, and one in which only a single amino acid change was made. What surprised researchers the most was that making that change to a single amino acid in Mre11 caused consequences as severe as when they eliminated the entire MRN complex. Taking out the amino acid in Mre11 responsible for nuclease activity caused the mice to develop growth defects, chromosomal abnormalities and sensitivity to DNA-damaging agents. Therefore, researchers could say that the nuclease, or repair, activity of Mre11 proves critical for both MRN function and stability of the genetic material of the organism. "First, Mre11 signals to the cell by activating the kinase, but it also acts in the repair of double-strand breaks via the nuclease functions. Therefore, it prevents the two individual steps that lead to cancer," Ferguson says. Implications The work, called "virtuoso cell engineering" in a Cell preview article, holds particular promise for identifying mutations associated with many 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 says. "This may have implications for diagnoses because tumors associated with different mutations may have different prognoses and respond to different therapies," he says. In particular, mutations in Mre11 may predict how sensitive or resistant a particular tumor will be to treatments with DNA-damaging agents. "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." Additional U-M authors are first author Jeffrey Buis, Yipin Wu, Jennifer Leddon, Gerwin Westfield, Mark Eckersdorff and JoAnn M. Sekiguchi. Funding for the research came from the National Institutes of Health, the Sidney Kimmel Cancer Research Foundation and the University of Michigan Cancer Center Support Grant and Munn Endowment. University of Michigan Health System |
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| Related Damaged Cells Current Events and Damaged Cells News Articles October 15, 2009 Loss of Tumor-Suppressor and DNA-Maintenance Proteins Causes Tissue Demise, Penn Study Finds A study published in the October issue of Nature Genetics demonstrates that loss of the tumor-suppressor protein p53, coupled with elimination of the DNA-maintenance protein ATR, severely disrupts tissue maintenance in mice. As a result, tissues deteriorate rapidly, which is generally fatal in these animals. In addition, the study provides supportive evidence for the use of inhibitors of ATR in cancer therapy. National Science Foundation congratulates Nobel Laureates in medicine/physiology, chemistry and economics The National Science Foundation (NSF) congratulates the 2009 Nobel laureates, particularly those who have received NSF funding over the years: Jack W. Szostak, who shared the prize in physiology or medicine; Thomas A. Steitz, who shared the prize in chemistry; and Elinor Ostrom and Oliver E. Williamson who earned the Sveriges Riksbank Prize in economic sciences in memory of Alfred Nobel 2009. 1 small step for neurons, 1 giant leap for nerve cell repair The repair of damaged nerve cells is a major problem in medicine today. A new study by researchers at the Montreal NeurologicaI Institute and Hospital (The Neuro) and McGill University, is a significant advance towards a solution for neuronal repair. Chemotherapy resistance: Checkpoint protein provides armor against cancer drugs Cell cycle checkpoints act like molecular tripwires for damaged cells, forcing them to pause and take stock. Study supports DNA repair-blocker research in cancer therapy Scientists at Dana-Farber Cancer Institute have uncovered the mechanism behind a promising new approach to cancer treatment: damaging cancer cells' DNA with potent drugs while simultaneously preventing the cells from repairing themselves. Stem cell research: From molecular physiology to therapeutic applications Stem cell research promises remedies to many devastating diseases that are currently incurable, ranging from diabetes and Parkinson's disease to paralysis. How the pathology of Parkinson's disease spreads Accumulation of the synaptic protein alpha-synuclein, resulting in the formation of aggregates called Lewy bodies in the brain, is a hallmark of Parkinson's and other related neurodegenerative diseases. New clue into how brain stem cells develop into cells which repair damaged tissue The joint research, funded by the National Multiple Sclerosis Society and the UK MS Society as well as the National Institutes of Health and Howard Hughes Medical Institute, was conducted by scientists at the University of California San Francisco (UCSF) and University of Cambridge and was published today (01 July) in the journal Genes and Development. BRIT1 allows DNA repair teams access to damaged sites Like a mechanic popping the hood of a car to get at a faulty engine, a tumor-suppressing protein allows cellular repair mechanisms to pounce on damaged DNA by overcoming a barrier to DNA access. Researchers identify biological markers that may indicate poor breast cancer prognosis A team of researchers has found an association between breast cancer survival and two proteins that, when present in the blood in high levels, are indicators of inflammation. More Damaged Cells Current Events and Damaged Cells News Articles |
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