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UBE2D3 facilitates NHEJ by orchestrating ATM signalling through multi-level control of RNF168.

التفاصيل البيبلوغرافية
العنوان: UBE2D3 facilitates NHEJ by orchestrating ATM signalling through multi-level control of RNF168.
المؤلفون: Yalçin Z; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., Lam SY; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., Peuscher MH; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., van der Torre J; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., Zhu S; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., Iyengar PV; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., Salas-Lloret D; Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands., de Krijger I; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., Moatti N; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., van der Lugt R; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., Falcone M; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., Cerutti A; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., Bleijerveld OB; Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., Hoekman L; Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands., González-Prieto R; Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands.; Andalusian Center for Molecular Biology and regenerative Medicine (CABIMER), Universidad de Sevilla-CSIC-Universidad-Pablo de Olavide, Sevilla, Spain.; Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain., Jacobs JJL; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands. j.jacobs@nki.nl.
المصدر: Nature communications [Nat Commun] 2024 Jun 12; Vol. 15 (1), pp. 5032. Date of Electronic Publication: 2024 Jun 12.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Ubiquitin-Conjugating Enzymes*/metabolism , Ubiquitin-Conjugating Enzymes*/genetics , Ataxia Telangiectasia Mutated Proteins*/metabolism , Ataxia Telangiectasia Mutated Proteins*/genetics , DNA End-Joining Repair* , Ubiquitin-Protein Ligases*/metabolism , Ubiquitin-Protein Ligases*/genetics , Signal Transduction* , Ubiquitination* , Tripartite Motif-Containing Protein 28*/metabolism , Tripartite Motif-Containing Protein 28*/genetics , Tumor Suppressor p53-Binding Protein 1*/metabolism , Tumor Suppressor p53-Binding Protein 1*/genetics, Humans ; Phosphorylation ; HEK293 Cells ; Telomere/metabolism ; DNA Damage ; Chromatin/metabolism ; Animals
مستخلص: Maintenance of genome integrity requires tight control of DNA damage response (DDR) signalling and repair, with phosphorylation and ubiquitination representing key elements. How these events are coordinated to achieve productive DNA repair remains elusive. Here we identify the ubiquitin-conjugating enzyme UBE2D3 as a regulator of ATM kinase-induced DDR that promotes non-homologous end-joining (NHEJ) at telomeres. UBE2D3 contributes to DDR-induced chromatin ubiquitination and recruitment of the NHEJ-promoting factor 53BP1, both mediated by RNF168 upon ATM activation. Additionally, UBE2D3 promotes NHEJ by limiting RNF168 accumulation and facilitating ATM-mediated phosphorylation of KAP1-S824. Mechanistically, defective KAP1-S824 phosphorylation and telomeric NHEJ upon UBE2D3-deficiency are linked to RNF168 hyperaccumulation and aberrant PP2A phosphatase activity. Together, our results identify UBE2D3 as a multi-level regulator of NHEJ that orchestrates ATM and RNF168 activities. Moreover, they reveal a negative regulatory circuit in the DDR that is constrained by UBE2D3 and consists of RNF168- and phosphatase-mediated restriction of KAP1 phosphorylation.
(© 2024. The Author(s).)
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معلومات مُعتمدة: KWF-NKI 2007-3907 KWF Kankerbestrijding (Dutch Cancer Society); KWF-NKI 2012-5305 KWF Kankerbestrijding (Dutch Cancer Society); KWF 12826/2019-2 KWF Kankerbestrijding (Dutch Cancer Society); institutional grant KWF Kankerbestrijding (Dutch Cancer Society); KWF-YIG 11367 KWF Kankerbestrijding (Dutch Cancer Society); H2020-MSCA-ITN-2018: 812829 EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions); institutional grant Ministerie van Volksgezondheid, Welzijn en Sport (Dutch Ministry of Health, Welfare and Sport); Netherlands X-omics Initiative Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research); Netherlands X-omics Initiative Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)
المشرفين على المادة: EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes)
EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
EC 2.3.2.27 (RNF168 protein, human)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
EC 2.3.2.27 (Tripartite Motif-Containing Protein 28)
EC 2.3.2.23 (UBE2D3 protein, human)
0 (Tumor Suppressor p53-Binding Protein 1)
EC 2.7.11.1 (ATM protein, human)
EC 2.3.2.27 (TRIM28 protein, human)
0 (TP53BP1 protein, human)
0 (Chromatin)
تواريخ الأحداث: Date Created: 20240612 Date Completed: 20240612 Latest Revision: 20240626
رمز التحديث: 20240626
مُعرف محوري في PubMed: PMC11169547
DOI: 10.1038/s41467-024-49431-6
PMID: 38866770
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-49431-6