PMID- 31353209
OWN - NLM
STAT- MEDLINE
DCOM- 20200129
LR  - 20200919
IS  - 1097-4164 (Electronic)
IS  - 1097-2765 (Print)
IS  - 1097-2765 (Linking)
VI  - 75
IP  - 6
DP  - 2019 Sep 19
TI  - Structural Basis for Target-Directed MicroRNA Degradation.
PG  - 1243-1255.e7
LID - S1097-2765(19)30475-7 [pii]
LID - 10.1016/j.molcel.2019.06.019 [doi]
AB  - MicroRNAs (miRNAs) broadly regulate gene expression through association with 
      Argonaute (Ago), which also protects miRNAs from degradation. However, miRNA 
      stability is known to vary and is regulated by poorly understood mechanisms. A 
      major emerging process, termed target-directed miRNA degradation (TDMD), employs 
      specialized target RNAs to selectively bind to miRNAs and induce their decay. 
      Here, we report structures of human Ago2 (hAgo2) bound to miRNAs and 
      TDMD-inducing targets. miRNA and target form a bipartite duplex with an unpaired 
      flexible linker. hAgo2 cannot physically accommodate the RNA, causing the duplex 
      to bend at the linker and display the miRNA 3' end for enzymatic attack. Altering 
      3' end display by changing linker flexibility, changing 3' end complementarity, 
      or mutationally inducing 3' end release impacts TDMD efficiency, leading to 
      production of distinct 3'-miRNA isoforms in cells. Our results uncover the 
      mechanism driving TDMD and reveal 3' end display as a key determinant regulating 
      miRNA activity via 3' remodeling and/or degradation.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Sheu-Gruttadauria, Jessica
AU  - Sheu-Gruttadauria J
AD  - Department of Integrative Structural and Computational Biology, The Scripps 
      Research Institute, La Jolla, CA 92037, USA.
FAU - Pawlica, Paulina
AU  - Pawlica P
AD  - Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical 
      Institute, Yale University School of Medicine, New Haven, CT 06536, USA.
FAU - Klum, Shannon M
AU  - Klum SM
AD  - Department of Integrative Structural and Computational Biology, The Scripps 
      Research Institute, La Jolla, CA 92037, USA.
FAU - Wang, Sonia
AU  - Wang S
AD  - Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical 
      Institute, Yale University School of Medicine, New Haven, CT 06536, USA.
FAU - Yario, Therese A
AU  - Yario TA
AD  - Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical 
      Institute, Yale University School of Medicine, New Haven, CT 06536, USA.
FAU - Schirle Oakdale, Nicole T
AU  - Schirle Oakdale NT
AD  - Department of Integrative Structural and Computational Biology, The Scripps 
      Research Institute, La Jolla, CA 92037, USA.
FAU - Steitz, Joan A
AU  - Steitz JA
AD  - Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical 
      Institute, Yale University School of Medicine, New Haven, CT 06536, USA. 
      Electronic address: joan.steitz@yale.edu.
FAU - MacRae, Ian J
AU  - MacRae IJ
AD  - Department of Integrative Structural and Computational Biology, The Scripps 
      Research Institute, La Jolla, CA 92037, USA. Electronic address: 
      macrae@scripps.edu.
LA  - eng
GR  - R01 GM115649/GM/NIGMS NIH HHS/United States
GR  - K99 GM129412/GM/NIGMS NIH HHS/United States
GR  - P01 CA016038/CA/NCI NIH HHS/United States
GR  - R35 GM127090/GM/NIGMS NIH HHS/United States
GR  - P41 GM103393/GM/NIGMS NIH HHS/United States
GR  - R01 CA193300/CA/NCI NIH HHS/United States
GR  - R01 GM104475/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190725
PL  - United States
TA  - Mol Cell
JT  - Molecular cell
JID - 9802571
RN  - 0 (AGO2 protein, human)
RN  - 0 (Argonaute Proteins)
RN  - 0 (MicroRNAs)
SB  - IM
MH  - Animals
MH  - Argonaute Proteins/genetics/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - MicroRNAs/genetics/*metabolism
MH  - *Nucleic Acid Conformation
MH  - *RNA Stability
MH  - Sf9 Cells
MH  - Spodoptera
PMC - PMC6754277
MID - NIHMS1535263
OTO - NOTNLM
OT  - Argonaute
OT  - HSUR1
OT  - TDMD
OT  - miRNA
OT  - miRNA-degradation
OT  - microRNA
OT  - tailing
OT  - trimming
COIS- DECLARATION OF INTERESTS Authors declare no competing interests.
EDAT- 2019/07/30 06:00
MHDA- 2020/01/30 06:00
PMCR- 2020/09/19
CRDT- 2019/07/30 06:00
PHST- 2019/01/14 00:00 [received]
PHST- 2019/05/08 00:00 [revised]
PHST- 2019/06/14 00:00 [accepted]
PHST- 2019/07/30 06:00 [pubmed]
PHST- 2020/01/30 06:00 [medline]
PHST- 2019/07/30 06:00 [entrez]
PHST- 2020/09/19 00:00 [pmc-release]
AID - S1097-2765(19)30475-7 [pii]
AID - 10.1016/j.molcel.2019.06.019 [doi]
PST - ppublish
SO  - Mol Cell. 2019 Sep 19;75(6):1243-1255.e7. doi: 10.1016/j.molcel.2019.06.019. Epub 
      2019 Jul 25.