title: Chromatin reader Brd4 functions in Ig class switching as a repair complex adaptor of nonhomologous end-joining.
abstract: Class switch recombination (CSR) is a B cell-specific genomic alteration induced by activation-induced cytidine deaminase (AID)-dependent DNA break at the immunoglobulin heavy-chain locus, followed by repair. Although chromatin-associated factors in promoting AID-induced DNA break have been widely reported, the involvement of chromatin adaptors at the repair phase of CSR remains unknown. Here, we show that the acetylated histone reader Brd4 is critical for nonhomologous end-joining (NHEJ) repair of AID- and I-SceI-induced DNA breaks. Brd4 was recruited to the DNA break regions, and its depletion from the chromatin caused CSR impairment without affecting the DNA break generation. Inhibition of Brd4 suppressed the accumulation of 53BP1 and uracil DNA glycosylase at the switch regions, perturbed the switch junctional microhomology, and reduced Igh/c-myc translocation. We conclude that Brd4 serves as a chromatin platform required for the recruitment of repair components during CSR and general DNA damage.
authors: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida Sakyo-ku, Kyoto 606-8501, Japan.
authors: Andre
authors: A
authors: Stanlie
authors: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida Sakyo-ku, Kyoto 606-8501, Japan.
authors: Ashraf S
authors: AS
authors: Yousif
authors: New Frontiers Research Laboratories, Toray Industries, Inc., Kanagawa 248-8555, Japan.
authors: Hideo
authors: H
authors: Akiyama
authors: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: honjo@mfour.med.kyoto-u.ac.jp.
authors: Tasuku
authors: T
authors: Honjo
authors: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida Sakyo-ku, Kyoto 606-8501, Japan.
authors: Nasim A
authors: NA
authors: Begum
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D059766:DNA End-Joining Repair; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011995:Recombination, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000092468:Bromodomain Containing Proteins
chemical_list: D002843:Chromatin; D009687:Nuclear Proteins; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins