Enzyme Inhibitor May Offer Dual Protection against Brain Disease 英文参考文献.docVIP

Synopsis EnzymeInhibitorMayOfferDualProtectionagainst BrainDisease CharlesQ.Choi* FreelanceScienceWriter,NewYork,NewYork,UnitedStatesofAmerica Chromosomesareextraordinarilylong, wigglystrands,makingupmorethantwo meters of DNA in each human cell, and given the 50 trillion or so cells in the human body, we have enough DNA in eachofustogofromheretothesunand back more than 300 times. To wrangle chromosomes into nuclei only ten to 20 micronswide,thesemoleculesare wound tightlyaroundproteinsknownashistones, compacting them by a factor of 10,000 duringcelldivision. half of yeast’s non-essential genes. Treat- ment with canavanine then revealed 11 mutantgenesthatcausedpersistentvulner- ability to the toxin, suggesting they might normallyhelpgeneraterepeats. Three of these genes were linked with enzymes known as histone deacetylases (HDACs),whichremoveacetylgroupsfrom histones. Knocking out any one of these genes reduced trinucleotide repeat expan- sionratesby50to90percent,confirming theirnormalabilitytohelpmutateDNA. To see what might happen in human cells, the scientists exposed lab-grown astrocytes—human nervous system cells thatareamongthetargetsofHuntington’s disease—toanHDACinhibitorknownas 4b. This suppressed trinucleotide repeat expansion rates by about 75 percent. Using RNA interference to knock down the enzyme HDAC3 in these cells had muchthesameeffect.Ontheotherhand, knockingdownenzymesknownashistone acetyltransferasesthataddacetylgroupsto histones, the opposite of HDACs, in- creasedexpansionfrequency. Bycontrollingaccesstogeneticmateri- al,histonesaremorethanjustspools,but caretakers as well. Now, Robert Lahue and his colleagues find enzymes that tamper with these guardians can warp the DNA wrapped around them, trigger- ingmutationsthatarethecauseofatleast 17 inherited neurological human disor- Combined actions of HDACs and DNA repair outweigh HATs, resulting in ex- pansions (a). But perturbing this situa- tion, for example, adding an HDAC inhibitor(b),ch