AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling

Mara H. Sherman, Ali I. Kuraishy, Chetan Deshpande, Jason S. Hong, Nicholas A. Cacalano, Richard A. Gatti, John P. Manis, Michael A. Damore, Matteo Pellegrini, Michael A. Teitell

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52 Scopus citations

Abstract

During an immune response, B cells undergo rapid proliferation and activation-induced cytidine deaminase (AID)-dependent remodeling of immunoglobulin (IG) genes within germinal centers (GCs) to generate memory B and plasma cells. Unfortunately, the genotoxic stress associated with the GC reaction also promotes most B cell malignancies. Here, we report that exogenous and intrinsic AID-induced DNA strand breaks activate ATM, which signals through an LKB1 intermediate to inactivate CRTC2, a transcriptional coactivator of CREB. Using genome-wide location analysis, we determined that CRTC2 inactivation unexpectedly represses a genetic program that controls GC B cell proliferation, self-renewal, and differentiation while opposing lymphomagenesis. Inhibition of this pathway results in increased GC B cell proliferation, reduced antibody secretion, and impaired terminal differentiation. Multiple distinct pathway disruptions were also identified in human GC B cell lymphoma patient samples. Combined, our data show that CRTC2 inactivation, via physiologic DNA damage response signaling, promotes B cell differentiation in response to genotoxic stress.

Original languageEnglish (US)
Pages (from-to)873-885
Number of pages13
JournalMolecular Cell
Volume39
Issue number6
DOIs
StatePublished - Sep 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Sherman, M. H., Kuraishy, A. I., Deshpande, C., Hong, J. S., Cacalano, N. A., Gatti, R. A., Manis, J. P., Damore, M. A., Pellegrini, M., & Teitell, M. A. (2010). AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling. Molecular Cell, 39(6), 873-885. https://doi.org/10.1016/j.molcel.2010.08.019