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A1: The role of the poly(A)-specific ribonuclease (PARN) in cellular RNA metabolism

Supervisor: Prof. Dr. Elmar Wahle

 

Specific aim(s)/topic(s) 

(1) The role of PARN in histone mRNA metabolism

(2) The role of PARN in cell stress

(3) Non-biased and comprehensive identification of PARN substrates

 

Background and significance

 RNA is subject to many processing and decay reactions involving 3' exonucleases. Both in processing and decay, exonucleases are influenced by the 3'-end addition of non-encoded nucleotides to their substrates. For example, long poly(A) tails are added to mRNA by the 'canonical' poly(A) polymerase, and their gradual removal by poly(A)-specific 3' exonucleases is the first and often rate-limiting step in mRNA decay. As subsequent steps of mRNA decay are delayed until deadenylation is more or less complete, mRNA poly(A) tails are stabilizing modifications. More recently, the end-addition of just a few A and sometimes U residues has been discovered. All kinds of RNA molecules can be substrates for this type of reaction, the responsible enzymes are 'non-canonical' poly(A)/poly(U) polymerases, and oligoadenylation/uridylation promotes either rapid decay of the modified RNA or its processing by a 3' exonuclease; in this sense, oligoadenylation/uridylation is a destabilizing modification. Three types of conserved poly(A)-specific 3' exonuclease complexes have been relatively well studied: The CCR4-NOT complex carries the major activity for mRNA deadenylation in all organisms analyzed. The PAN complex plays a similar but supporting role. The role of the homodimeric poly(A)-specific ribonuclease (PARN) is less well understood. Its preference for poly(A) and a modest stimulation by a 5' cap on the substrate suggest mRNAs as substrates. However, several studies have not found a role in general mRNA decay. Functions in the degradation of a few specific mRNAs and under certain stress conditions have been suggested.