Molecular Cell
Volume 55, Issue 1, 3 July 2014, Pages 97-110
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Article
Chromatin Reader Brd4 Functions in Ig Class Switching as a Repair Complex Adaptor of Nonhomologous End-Joining

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Highlights

  • Brd4 is required for AID-induced CSR, but not SHM

  • Brd4 accumulates at DNA breaks induced by either AID or I-SceI

  • Brd4 recruits repair factors to the S region chromatin containing H4Ac and γH2AX

  • Brd4 repair complex is required for NHEJ after AID- or I-SceI-induced DNA cleavage

Summary

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.

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