ArticleThe Journal of biological chemistry2016
Identification and Characterization of MCM3 as a Kelch-like ECH-associated Protein 1 (KEAP1) Substrate.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 84 citations in OpenAlex.
- USP1 promotes hepatocellular carcinoma progression by modulating mitophagy via stabilizing MCM3 to regulate the Keap1-Nrf2 axis.iScience · 2026Article
- Linked-domain inhibitors designed to block UBE2D induce the unfolded protein response.Cell chemical biology · 2025Article
- Activating NRF2Cancer gene therapy · 2025Article
- KEAP1-NRF2 Interaction in Cancer: Competitive Interactors and Their Role in Carcinogenesis.Cancers · 2025Review
- Uncovering Cell Cycle Dysregulations and Associated Mechanisms in Cancer and Neurodegenerative Disorders: A Glimpse of Hope for Repurposed Drugs.Molecular neurobiology · 2024Review
- Design of linked-domain protein inhibitors of UBE2D as tools to study cellular ubiquitination.bioRxiv : the preprint server for biology · 2024Article
- Genome-Wide CRISPR Screen Identifies KEAP1 Perturbation as a Vulnerability of ARID1A-Deficient Cells.Cancers · 2024Article
- Nrf2 activation by pyrroloquinoline quinone inhibits natural aging-related intervertebral disk degeneration in mice.Aging cell · 2024Article
- Unwinding Helicase MCM Functionality for Diagnosis and Therapeutics of Replication Abnormalities Associated with Cancer: A Review.Molecular diagnosis & therapy · 2024Review
- Rac GTPase activating protein 1 promotes the glioma growth by regulating the expression of MCM3.Translational oncology · 2023Article
- Exogenous HCell death discovery · 2023Article
- Pyrroloquinoline quinone alleviates natural aging-related osteoporosis via a novel MCM3-Keap1-Nrf2 axis-mediated stress response and Fbn1 upregulation.Aging cell · 2023Article
- The assembly of the MCM2-7 hetero-hexamer and its significance in DNA replication.Biochemical Society transactions · 2023Review
- Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression.Cancer research · 2023Article
- Review
- Review
- Superenhancer activation of KLHDC8A drives glioma ciliation and hedgehog signaling.The Journal of clinical investigation · 2023Article
- STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Novel protein contact points among TP53 and minichromosome maintenance complex proteins 2, 3, and 5.Cancer medicine · 2022Article
- Keap1 moderates the transcription of virus induced genes through G9a-GLP and NFκB p50 recruitment.Immunology · 2022Article
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
KEAP1 is a substrate adaptor protein for a CUL3-based E3 ubiquitin ligase. Ubiquitylation and degradation of the antioxidant transcription factor NRF2 is considered the primary function of KEAP1; however, few other KEAP1 substrates have been identified. Because KEAP1 is altered in a number of human pathologies and has been proposed as a potential therapeutic target therein, we sought to better understand KEAP1 through systematic identification of its substrates. Toward this goal, we combined parallel affinity capture proteomics and candidate-based approaches. Substrate-trapping proteomics yielded NRF2 and the related transcription factor NRF1 as KEAP1 substrates. Our targeted investigation of KEAP1-interacting proteins revealed MCM3, an essential subunit of the replicative DNA helicase, as a new substrate. We show that MCM3 is ubiquitylated by the KEAP1-CUL3-RBX1 complex in cells and in vitro Using ubiquitin remnant profiling, we identify the sites of KEAP1-dependent ubiquitylation in MCM3, and these sites are on predicted exposed surfaces of the MCM2-7 complex. Unexpectedly, we determined that KEAP1 does not regulate total MCM3 protein stability or subcellular localization. Our analysis of a KEAP1 targeting motif in MCM3 suggests that MCM3 is a point of direct contact between KEAP1 and the MCM hexamer. Moreover, KEAP1 associates with chromatin in a cell cycle-dependent fashion with kinetics similar to the MCM2-7 complex. KEAP1 is thus poised to affect MCM2-7 dynamics or function rather than MCM3 abundance. Together, these data establish new functions for KEAP1 within the nucleus and identify MCM3 as a novel substrate of the KEAP1-CUL3-RBX1 E3 ligase.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.