PT  - JOURNAL ARTICLE
AU  - Feng He
AU  - Chan Wu
AU  - Allan Jacobson
TI  - Dcp2 C-terminal <em>Cis</em>-Binding Elements Control Selective Targeting of the Decapping Enzyme by Forming Distinct Decapping Complexes
AID  - 10.1101/2021.10.01.462794
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.10.01.462794
4099  - http://biorxiv.org/content/early/2021/10/01/2021.10.01.462794.short
4100  - http://biorxiv.org/content/early/2021/10/01/2021.10.01.462794.full
AB  - A single Dcp1-Dcp2 decapping enzyme targets diverse classes of yeast mRNAs for decapping-dependent 5’ to 3’ decay, but the molecular mechanisms controlling selective mRNA targeting by the enzyme remain elusive. Through extensive genetic analyses we uncover cis-regulatory elements in the Dcp2 C-terminal domain that control selective targeting of the decapping enzyme by forming distinct decapping complexes. Two Upf1-binding motifs target the decapping enzyme to NMD substrates, and a single Edc3-binding motif targets both Edc3 and Dhh1 substrates. Pat1-binding leucine-rich motifs target Edc3 and Dhh1 substrates under selective conditions. Although it functions as a unique targeting component of specific complexes, Edc3 is a common component of multiple complexes. Xrn1 also has a specific Dcp2 binding site, allowing it to be directly recruited to decapping complexes. Collectively, our results demonstrate that Upf1, Edc3, and Pat1 function as regulatory subunits of the holo-decapping enzyme, controlling both its targeting specificity and enzymatic activation.Highlights Loss of Dcp2 cis-binding elements causes selective stabilization of distinct decapping substratesDcp2 cis-binding elements promote the assembly of target-specific decapping complexes in vivoXrn1 binds to Dcp2, and both Edc3 and Xrn1 are common components of multiple decapping complexesUpf1, Edc3, and Pat1 function as unique targeting subunits of the yeast holo-decapping enzymeCompeting Interest StatementA.J. is co-founder, director, and SAB chair of PTC Therapeutics Inc. All other authors declare no competing interests.