A Damage-Independent Role for 53BP1 that Impacts Break Order and Igh Architecture during Class Switch Recombination

Pedro P. Rocha, Ramya Raviram, Yi Fu, Jung Hyun Kim, Vincent M. Luo, Arafat Aljoufi, Emily Swanzey, Alessandra Pasquarella, Alessia Balestrini, Emily R. Miraldi, Richard Bonneau, John Petrini, Gunnar Schotta, Jane A. Skok

Research output: Contribution to journalArticle

Abstract

During class switch recombination (CSR), B cells replace the Igh Cμ or δ exons with another downstream constant region exon (CH), altering the antibody isotype. CSR occurs through the introduction of AID-mediated double-strand breaks (DSBs) in switch regions and subsequent ligation of broken ends. Here, we developed an assay to investigate the dynamics of DSB formation in individual cells. We demonstrate that the upstream switch region Sμ is first targeted during recombination and that the mechanism underlying this control relies on 53BP1. Surprisingly, regulation of break order occurs through residual binding of 53BP1 to chromatin before the introduction of damage and independent of its established role in DNA repair. Using chromosome conformation capture, we show that 53BP1 mediates changes in chromatin architecture that affect break order. Finally, our results explain how changes in Igh architecture in the absence of 53BP1 could promote inversional rearrangements that compromise CSR.

Original languageEnglish (US)
Pages (from-to)48-55
Number of pages8
JournalCell Reports
Volume16
Issue number1
DOIs
StatePublished - Jun 28 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Rocha, P. P., Raviram, R., Fu, Y., Kim, J. H., Luo, V. M., Aljoufi, A., Swanzey, E., Pasquarella, A., Balestrini, A., Miraldi, E. R., Bonneau, R., Petrini, J., Schotta, G., & Skok, J. A. (2016). A Damage-Independent Role for 53BP1 that Impacts Break Order and Igh Architecture during Class Switch Recombination. Cell Reports, 16(1), 48-55. https://doi.org/10.1016/j.celrep.2016.05.073