The Sound of a Silent Mutation - ScienceNOW - Courses

The Sound of a Silent Mutation - ScienceNOWhttp://news.sciencemag.org/sciencenow/2006/12/22-02.htmlAAAS.ORG FEEDBACK HELP LIBRARIANS Daily News Enter Search Term ADVANCEDALERTS ACCESS RIGHTS MY ACCOUNT SIGN INNews Home ScienceNOW ScienceInsider Premium Content from Science About Science NewsHome > News > ScienceNOW > December 2006 > The Sound of a Silent MutationADVERTISEMENTThe Sound of a Silent Mutationby Mary Beckman on December 22, 2006 12:00 AM | Permanent Link | 0 CommentsEmail Print | More PREVIOUS ARTICLE NEXT ARTICLEADVERTISEMENT1 of 3 5/9/10 9:59 AM

The Sound of a Silent Mutation - ScienceNOWhttp://news.sciencemag.org/sciencenow/2006/12/22-02.htmlAnother dogma in cell biology seems about to be toppled: If a mutation in agene doesn't change the basic sequence of building blocks, then it has noeffect. Chava Kimchi-Sarfaty of the U.S. Food and Drug Administration inBethesda, Maryland, and colleagues report online this week in Sciencethat such "silent mutations" can, under certain circumstances, determinehow well a final protein performs--an "extremely provocative" result, sayscell biologist William Skach of Oregon Health & Science University inPortland.Silent mutations occur when the change of a single DNA nucleotide withina protein-coding portion of a gene does not affect the sequence of aminoacids that make up the gene's protein. That's possible because proteinsare encoded by "triplets" of nucleotides, each responsible for adding aparticular amino acid to the protein chain. A change in one nucleotide,ENLARGE IMAGENoise.The normal gene for P-gp (left) and atriple mutant (right) make the sameamount of protein in the cell. But theprotein's structure and function arealtered.Credit: C. Kimchi-Sarfaty et al.however, doesn't always change the triplet's meaning; the mutated triplet may still add the same amino acid. Andwhen the amino acids of a protein stay the same, researchers believed, so do its structure and function.But every once in a while, data crop up that don't make sense; for example, a gene called multidrug resistance-1(MDR-1) has been found to frequently have a particular silent mutation in human cancer cells. MDR-1 producesP-gp, a protein that pumps chemotherapy drugs out of cancer cells, thus making the drugs useless. Researcherswondered why the silent mutation, called C3435T, showed up much more frequently than expected for a change thatdoesn't have an effect on the cancer cells' survival.Kimchi-Sarfaty's team made cell lines that had either the normal MDR-1 gene, a version with the C3435T mutation,versions with either of two other mutations known to occur sometimes along with C3435T (one of them silent as well,the other nonsilent but without an effect on protein function), and versions with various combinations of two or threeof the mutations.They found that the mutations individually appeared to have no effect: The P-gp proteins encoded by each genevariant were just as proficient at pumping drugs out of cells. But cells with the MDR-1 gene containing the C3435Tmutation plus one or two of the other two mutations did a much better job of ridding cancer cells of the drugs,allowing the cells to live another day.How is this possible if the variant P-gp has the same string of amino acids as the normal one? To the researchers'surprise, a biochemical test suggested that the mutant P-gp has a slightly different three-dimensional shape.Perhaps, Kimchi-Sarfaty says, the silent mutations reside in nucleotide triplets that cells don't use very often, whichcould slow down the cell's proteinmaking machinery. Like designs made with Silly String spraying out at differentvelocities, the folding of an amino acid chain into a 3D structure is somewhat speed-dependent, and slowerproduction could cause the protein to take an altered final form. The cell might be able to compensate for one silentmutation but not for multiple rarely used triplets.The idea that silent mutations might have such effects is "an entirely new concept," Skach says. His prediction: Moreresearchers will start listening to what silent mutations have to say.Email Print | 0 0 tweet Share MoreLoginShareYour name (required)This PageWhat's on your mind...Add imagesFollowCancelPostEcho 0 ItemsAdminSocial Networking by2 of 3 5/9/10 9:59 AM

The Sound of a Silent Mutation - ScienceNOWhttp://news.sciencemag.org/sciencenow/2006/12/22-02.html3 of 3 5/9/10 9:59 AM