Affinage

LRR1

Leucine-rich repeat protein 1 · UniProt Q96L50

Length
414 aa
Mass
46.7 kDa
Annotated
2026-06-10
11 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRR1 is the substrate-recognition subunit of the CRL2(LRR1) cullin-RING E3 ubiquitin ligase that governs replisome disassembly during DNA replication termination (PMID:28235849, PMID:28368371). CRL2(LRR1) ubiquitylates the MCM7 subunit of the CMG (CDC45-MCM-GINS) replicative helicase specifically at termination, and this neddylation-dependent ubiquitylation triggers p97/CDC-48-driven (UFD-1/NPL-4-assisted) unloading of CMG and its associated replisome from chromatin (PMID:28235849, PMID:28368371). This activity is conserved across Xenopus egg extracts, C. elegans, mouse embryonic stem cells and human cells, where a parallel TRAIP-dependent route handles mitotic CMG disassembly (PMID:28368371, PMID:33590678). In human cells LRR1 is essential for cell division: its loss blocks CMG unloading, causes replisome components to accumulate on chromatin throughout S phase and sequesters rate-limiting replisome factors, slowing replication and provoking ATR-dependent G2/M checkpoint arrest (PMID:34037657). The ubiquitin mark written by CRL2(LRR1) at active forks is reversed by the USP37 deubiquitylase, which binds the CMG subunit CDC45 through its PH domain to protect ongoing forks from premature disassembly under replication stress (PMID:40411782). Beyond replication, CRL2(LRR1) promotes cell-cycle progression by targeting Cip/Kip CDK inhibitors for degradation—CKI-1 in the C. elegans germline and cytoplasmic p21 in human cells, the latter linking the ligase to Rho/ROCK/LIMK-cofilin actin remodeling and cell motility (PMID:21074724).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2010 High

    Before its replication role was known, LRR1 was established as a substrate-recognition subunit of a CRL2 ligase that degrades CDK inhibitors, answering how it influences cell-cycle progression and, in human cells, actin dynamics.

    Evidence RNAi in C. elegans and human cells with Co-IP, ubiquitylation assays and cell motility/actin imaging

    PMID:21074724

    Open questions at the time
    • Does not address any role in DNA replication or CMG helicase regulation
    • Mechanism linking cytoplasmic p21 to Rho/ROCK shown by pathway epistasis, not direct biochemistry
  2. 2013 Medium

    Extended the CRL2(LRR-1) substrate repertoire in the germline, showing it gates the mitosis-to-meiosis decision by degrading the HORMA protein HTP-3 and counteracting the ATL-1 replication checkpoint.

    Evidence Temperature-sensitive cul-2 mutants, genetic epistasis and HTP-3 stability Westerns in C. elegans

    PMID:23555289

    Open questions at the time
    • Single organism and single lab
    • Direct ubiquitylation of HTP-3 by CRL2(LRR-1) not reconstituted
  3. 2017 High

    Defined the core conserved function: CRL2(LRR1) ubiquitylates CMG-MCM7 specifically at replication termination to trigger replisome unloading, answering how the replicative helicase is removed from completed DNA.

    Evidence Proteomic screen and depletion in Xenopus egg extracts plus genetic inactivation in C. elegans, with chromatin fractionation, ubiquitylation readouts and CDC-48 cofactor/neddylation epistasis

    PMID:28235849 PMID:28368371

    Open questions at the time
    • Did not establish requirement in mammalian cells
    • Structural basis of MCM7 recognition by LRR1 not resolved
  4. 2021 High

    Established that the LRR1/CMG-disassembly pathway operates in mammalian cells and is essential, defining two parallel ubiquitin-ligase routes (CRL2(LRR1) in S phase, TRAIP in mitosis) and linking failed unloading to replication slowdown and ATR-dependent G2/M arrest.

    Evidence Auxin-inducible degron and CRISPR/siRNA depletion in mouse ES cells and human cells with chromatin fractionation, MCM7 ubiquitylation, replication-rate and checkpoint assays plus live imaging

    PMID:33590678 PMID:34037657

    Open questions at the time
    • Identity of rate-limiting recycled replisome factors not fully enumerated
    • How chromatin recruitment of CRL2(LRR1) is timed to termination remains undefined
  5. 2025 High

    Identified the counter-regulator: USP37 deubiquitylates CMG to oppose CRL2(LRR1) at active forks, defining LRR1 as the ubiquitin writer whose reversal protects forks during replication stress.

    Evidence Reciprocal Co-IP of USP37 with CMG, structure-guided PH-domain mutagenesis, and genetic epistasis (CUL2LRR1 depletion suppressing USP37-mutant stress sensitivity) in human cells

    PMID:40411782

    Open questions at the time
    • Direct demonstration that USP37 removes the specific CRL2(LRR1)-deposited MCM7 chain not shown
    • Spatiotemporal switch favoring writing versus erasing at termination vs. active forks unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CRL2(LRR1) discriminates terminated from active forks, and how its chromatin recruitment is restricted to termination, remains the central open mechanistic question.
  • No structural model of LRR1-MCM7 recognition
  • Determinants of termination-specific recruitment unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005694 chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-69306 DNA Replication 4 R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CDC45CDKN1ACKI-1CUL2HTP-3MCM7TNFRSF9USP37
Complex memberships
CRL2(LRR1) E3 ubiquitin ligase

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 CRL2Lrr1 (CUL2 E3 ubiquitin ligase with LRR1 as substrate-recognition subunit) ubiquitylates the MCM7 subunit of the CMG helicase specifically during DNA replication termination in Xenopus egg extracts; in its absence, Mcm7 is not ubiquitylated, CMG unloading is inhibited, and a large replisome subcomplex including DNA Pol ε is retained on chromatin. Proteomic screen in Xenopus egg extracts combined with depletion of CRL2Lrr1 and functional readouts of CMG unloading and Mcm7 ubiquitylation Genes & development High 28235849
2017 CUL-2LRR-1 associates with the replisome and drives ubiquitylation and disassembly of the CMG helicase in both C. elegans embryos and Xenopus egg extracts, acting together with CDC-48 cofactors UFD-1 and NPL-4; chromatin recruitment of CUL2LRR1 is a key regulated step during DNA replication termination, and CUL2 neddylation is required for CMG removal from chromatin. Genetic inactivation in C. elegans combined with biochemical assays in Xenopus egg extracts; epistasis with CDC-48 cofactors; neddylation inhibition Nature cell biology High 28368371
2010 CRL2(LRR-1) ubiquitin ligase promotes degradation of the Cip/Kip CDK inhibitor CKI-1 in C. elegans germline nuclei to drive G1-phase cell cycle progression, and targets cytoplasmic p21 (CDKN1A) in human cells; loss of human CRL2(LRR1) prevents cytoplasmic p21 degradation, leading to p21-mediated inhibition of the Rho/ROCK/LIMK pathway, activation of the actin-depolymerizing protein cofilin, actin cytoskeleton reorganization, and increased cell motility. RNAi knockdown in C. elegans and human cells; co-immunoprecipitation; ubiquitylation assays; actin cytoskeleton imaging; cell motility assays Developmental cell High 21074724
2013 CRL2(LRR-1) in C. elegans promotes germ cell proliferation by counteracting the ATL-1 DNA replication checkpoint pathway, participates in the mitotic proliferation/meiotic entry decision, and inhibits early meiotic prophase by targeting the HORMA-domain protein HTP-3 for degradation, thereby preventing loading of synaptonemal complex components onto meiotic chromosomes. Temperature-sensitive cul-2 mutant analysis; genetic epistasis with ATL-1 checkpoint; Western blot for HTP-3 stability; cytological analysis of meiotic progression PLoS genetics Medium 23555289
2021 In mouse embryonic stem cells, CUL2LRR1 is required for ubiquitylation of CMG-MCM7 during S-phase and subsequent p97-dependent replisome disassembly; a parallel mitotic pathway for CMG disassembly depends on the TRAIP ubiquitin ligase, establishing that metazoan replisome disassembly is regulated by two conserved ubiquitin ligases. Auxin-inducible degron depletion of CUL2LRR1 and TRAIP in mouse ES cells; chromatin fractionation; MCM7 ubiquitylation assays; cell cycle analysis EMBO reports High 33590678
2021 In human cells, LRR1 loss prevents CMG helicase unloading from chromatin; chromatin-bound replisome components accumulate throughout S phase, sequestering rate-limiting replisome factors and slowing DNA replication; persistent chromatin-bound CMG in G2 activates ATR-mediated G2/M checkpoint and blocks mitosis; LRR1 is an essential gene for human cell division. siRNA and CRISPR knockout of LRR1 in human cells; live-cell imaging; DNA replication rate assays; chromatin fractionation; ATR checkpoint activation assays The Journal of cell biology High 34037657
2025 USP37 deubiquitylase counteracts CMG helicase ubiquitylation by CUL2LRR1: USP37 binds CDC45 (a CMG subunit) via its Pleckstrin-Homology domain at replication forks, and depletion of CUL2LRR1 suppresses the DNA replication stress sensitivity of USP37 mutants, placing CUL2LRR1 as the ubiquitin writer whose activity is reversed by USP37 to protect ongoing replication forks. Co-immunoprecipitation of USP37 with CMG; structure-guided mutagenesis of USP37 PH domain; genetic epistasis (CUL2LRR1 depletion suppressing Usp37 mutant phenotypes); sensitivity assays to DNA synthesis inhibitors and ATR inhibitors Cell reports High 40411782
2001 LRR-1 protein specifically interacts with the cytoplasmic domain of 4-1BB (TNFR superfamily member) as identified by yeast two-hybrid screening; overexpression of LRR-1 suppresses NF-κB activation induced by 4-1BB or TRAF2, and down-regulates JNK1 activity induced by 4-1BB, indicating LRR-1 negatively regulates 4-1BB-mediated signaling cascades. Yeast two-hybrid screening; overexpression with NF-κB reporter assay; JNK1 kinase activity assay Molecules and cells Low 11804328

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 CRL2Lrr1 promotes unloading of the vertebrate replisome from chromatin during replication termination. Genes & development 97 28235849
2017 CUL-2LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis. Nature cell biology 90 28368371
2010 CRL2(LRR-1) targets a CDK inhibitor for cell cycle control in C. elegans and actin-based motility regulation in human cells. Developmental cell 53 21074724
2013 CRL2(LRR-1) E3-ligase regulates proliferation and progression through meiosis in the Caenorhabditis elegans germline. PLoS genetics 35 23555289
2021 CUL2LRR1 , TRAIP and p97 control CMG helicase disassembly in the mammalian cell cycle. EMBO reports 32 33590678
2001 A novel leucine-rich repeat protein (LRR-1): potential involvement in 4-1BB-mediated signal transduction. Molecules and cells 27 11804328
2021 LRR1-mediated replisome disassembly promotes DNA replication by recycling replisome components. The Journal of cell biology 18 34037657
2017 Silencing of the Rice Gene LRR1 Compromises Rice Xa21 Transcript Accumulation and XA21-Mediated Immunity. Rice (New York, N.Y.) 10 28534133
2020 The Protective Effect of Low Dose of Lipopolysaccharide Pretreatment on Endotoxin-Induced Uveitis in Rats Is Associated with Downregulation of CSF-1 and Upregulation of LRR-1. Journal of immunology research 5 32671118
2025 USP37 protects mammalian cells during DNA replication stress by counteracting CUL2LRR1 and TRAIP. Cell reports 4 40411782
2013 Role of the CRL2(LRR-1) E3 ubiquitin-ligase in the development of the germline in C. elegans. Worm 2 24778939

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