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Title: Multi-domain utilization by TUT4 and TUT7 in control of let-7 biogenesis

Abstract

The uridyl transferases TUT4 and TUT7 (collectively called TUT4(7)) switch between two modes of activity, either promoting expression of let-7 microRNA (monoU) or marking it for degradation (oligoU). Lin28 modulates the switch via recruitment of TUT4(7) to the precursor pre-let-7 in stem cells and human cancers. We found that TUT4(7) utilize two multidomain functional modules during the switch from monoU to oligoU. The catalytic module (CM) is essential for both activities, while the Lin28-interacting module (LIM) is indispensable for oligoU. A TUT7 CM structure trapped in the monoU activity staterevealed a duplex-RNA-binding pocket that orients group II pre-let-7 hairpins to favor monoU addition. Conversely, the switch to oligoU requires the ZK domain of Lin28 to drive the formation of a stable ternary complex between pre-let-7 and the inactive LIM. Finally, ZK2 of TUT4(7) aids oligoU addition by engaging the growing oligoU tail through uracil-specific interactions.

Authors:
; ; ORCiD logo
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1409573
Report Number(s):
BNL-114625-2017-JA¿¿¿
Journal ID: ISSN 1545-9993
DOE Contract Number:  
SC0012704
Resource Type:
Journal Article
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 24; Journal Issue: 8; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Faehnle, Christopher R., Walleshauser, Jack, and Joshua-Tor, Leemor. Multi-domain utilization by TUT4 and TUT7 in control of let-7 biogenesis. United States: N. p., 2017. Web. doi:10.1038/nsmb.3428.
Faehnle, Christopher R., Walleshauser, Jack, & Joshua-Tor, Leemor. Multi-domain utilization by TUT4 and TUT7 in control of let-7 biogenesis. United States. doi:10.1038/nsmb.3428.
Faehnle, Christopher R., Walleshauser, Jack, and Joshua-Tor, Leemor. Mon . "Multi-domain utilization by TUT4 and TUT7 in control of let-7 biogenesis". United States. doi:10.1038/nsmb.3428.
@article{osti_1409573,
title = {Multi-domain utilization by TUT4 and TUT7 in control of let-7 biogenesis},
author = {Faehnle, Christopher R. and Walleshauser, Jack and Joshua-Tor, Leemor},
abstractNote = {The uridyl transferases TUT4 and TUT7 (collectively called TUT4(7)) switch between two modes of activity, either promoting expression of let-7 microRNA (monoU) or marking it for degradation (oligoU). Lin28 modulates the switch via recruitment of TUT4(7) to the precursor pre-let-7 in stem cells and human cancers. We found that TUT4(7) utilize two multidomain functional modules during the switch from monoU to oligoU. The catalytic module (CM) is essential for both activities, while the Lin28-interacting module (LIM) is indispensable for oligoU. A TUT7 CM structure trapped in the monoU activity staterevealed a duplex-RNA-binding pocket that orients group II pre-let-7 hairpins to favor monoU addition. Conversely, the switch to oligoU requires the ZK domain of Lin28 to drive the formation of a stable ternary complex between pre-let-7 and the inactive LIM. Finally, ZK2 of TUT4(7) aids oligoU addition by engaging the growing oligoU tail through uracil-specific interactions.},
doi = {10.1038/nsmb.3428},
journal = {Nature Structural & Molecular Biology},
issn = {1545-9993},
number = 8,
volume = 24,
place = {United States},
year = {2017},
month = {7}
}

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