Exonuclease-mediated degradation of nascent RNA

Antigenic variation of the Plasmodium falciparum multicopy var genefamilyenablesparasiteevasionofimmunedestructionbyhost antibodies 1,2 .Expressionofaparticular var subgroup,termed upsA ,islinkedtotheobstructionofbloodvesselsinthebrainandtothepath-ogenesisofhumancerebralmalaria 3–6 .Themechanismdetermining upsA activation remains unknown. Here we show that an entirely

new type of gene silencing mechanism involving an exonuclease-mediateddegradationofnascentRNAcontrolsthesilencingofgenes linked to severe malaria. We identify a novel chromatin-associated exoribonuclease, termed PfRNaseII, that controls the silencing of upsAvar genesbymarkingtheirtranscriptionstartsiteandintron-promoterregionsleadingtoshort-livedcrypticRNA.Parasitescarry-

ingadeficient PfRNaseII geneproducefull-length upsAvar transcripts andintron-derivedantisenselongnon-codingRNA.Thepresenceof stable upsA var transcripts overcomes monoallelic expression, re-sultinginthesimultaneousexpressionofboth upsA and upsC type PfEMP1 proteins on the surface of individual infected red blood cells. 

lencegenesinvolvedinpathogenesisinpatientswithseveremalaria may provide new strategies for reducing malaria mortality