title: BCL10 regulates RNF8/RNF168-mediated ubiquitination in the DNA damage response.
abstract: Timely and proper cellular response to DNA damage is essential for maintenance of genome stability and integrity. B-cell lymphoma/leukemia 10 (BCL10) facilitates ubiquitination of NEMO in the cytosol, activating NFκB signaling. Translocation and/or point mutations of BCL10 associate with mucosa-associated lymphoid tissue lymphomas and other malignancies. However, the mechanisms by which the resulting aberrant expression of BCL10 leads to cellular oncogenesis are poorly understood. In this report, we found that BCL10 in the nucleus is enriched at the DNA damage sites in an ATM- and RNF8-dependent manner. ATM-dependent phosphorylation of BCL10 promotes its interaction with and presentation of UBC13 to RNF8, and RNF8-mediated ubiquitination of BCL10 enhances binding of BCL10 and UBC13 to RNF168. This allows mono-ubiquitination on H2AX by RNF168 and further poly-ubiquitination by the RNF8/RNF168-containing complex. Depletion of BCL10 compromised homology recombination-mediated DNA double-strand break (DSB) repair because of insufficient recruitment of BRCA1, RAD51, and the ubiquitinated DNA damage response factors. Taken together, our results demonstrate a novel function of BCL10 in delivering UBC13 to RNF8/RNF168 to regulate ubiquitination-mediated DSB signaling and repair.
authors.affiliation: Beijing Key Laboratory of DNA Damage Response and College of Life Science; Capital Normal University; Beijing, China.
authors.forename: Hongchang
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Beijing Key Laboratory of DNA Damage Response and College of Life Science; Capital Normal University; Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Beijing Key Laboratory of DNA Damage Response and College of Life Science; Capital Normal University; Beijing, China.
authors.forename: Gelin
authors.initials: G
authors.lastname: Dou
authors.affiliation: Beijing Key Laboratory of DNA Damage Response and College of Life Science; Capital Normal University; Beijing, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Beijing Key Laboratory of DNA Damage Response and College of Life Science; Capital Normal University; Beijing, China.
authors.forename: Bingtao
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Beijing Key Laboratory of DNA Damage Response and College of Life Science; Capital Normal University; Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Beijing Key Laboratory of DNA Damage Response and College of Life Science; Capital Normal University; Beijing, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Liao
authors.affiliation: Beijing Key Laboratory of DNA Damage Response and College of Life Science; Capital Normal University; Beijing, China.
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Xu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D047468:Immunoprecipitation; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; C491731:IKBKG protein, human; D016328:NF-kappa B; D009841:Oligonucleotides; D034741:RNA, Small Interfering; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase
keywords: BCL10; DNA damage; RNF168; RNF8; ubiquitination
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