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Insert L1 is a central hub for allosteric regulation of USP1 activity
Author(s) -
Dharadhar Shreya,
Dijk Willem J,
Scheffers Serge,
Fish Alexander,
Sixma Titia K
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202051749
Subject(s) - allosteric regulation , deubiquitinating enzyme , ubiquitin , activator (genetics) , proliferating cell nuclear antigen , dna , microbiology and biotechnology , polymerase , dna replication , insert (composites) , biology , chemistry , enzyme , biochemistry , gene , materials science , composite material
Abstract During DNA replication, the deubiquitinating enzyme USP1 limits the recruitment of translesion polymerases by removing ubiquitin marks from PCNA to allow specific regulation of the translesion synthesis (TLS) pathway. USP1 activity depends on an allosteric activator, UAF1, and this is tightly controlled. In comparison to paralogs USP12 and USP46, USP1 contains three defined inserts and lacks the second WDR20‐mediated activation step. Here we show how inserts L1 and L3 together limit intrinsic USP1 activity and how this is relieved by UAF1. Intriguingly, insert L1 also conveys substrate‐dependent increase in USP1 activity through DNA and PCNA interactions, in a process that is independent of UAF1‐mediated activation. This study establishes insert L1 as an important regulatory hub within USP1 necessary for both substrate‐mediated activity enhancement and allosteric activation upon UAF1 binding.