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Mol Cell. 2010 Sep 24;39(6):873-85. doi: 10.1016/j.molcel.2010.08.019.

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

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1
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

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.

PMID:
20864035
PMCID:
PMC2945612
DOI:
10.1016/j.molcel.2010.08.019
[Indexed for MEDLINE]
Free PMC Article

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