AID-Induced Genotoxic Stress Promotes B Cell Differentiation in the Germinal Center via ATM and LKB1 Signaling

• Published in: Molecular cell 2010-09, Vol.39 (6), p.873-885
• Main Authors: Sherman, Mara H., Kuraishy, Ali I., Deshpande, Chetan, Hong, Jason S., Cacalano, Nicholas A., Gatti, Richard A., Manis, John P., Damore, Michael A., Pellegrini, Matteo, Teitell, Michael A.
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - radiation effects; Animals; Ataxia Telangiectasia Mutated Proteins; B-Lymphocytes - cytology; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; B-Lymphocytes - radiation effects; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Differentiation - drug effects; Cell Differentiation - immunology; Cell Differentiation - radiation effects; Cell Line, Tumor; Cytidine Deaminase - genetics; DNA Breaks, Double-Stranded - drug effects; DNA Breaks, Double-Stranded - radiation effects; DNA Damage - drug effects; DNA Damage - immunology; DNA Damage - radiation effects; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression - drug effects; Gene Expression - immunology; Gene Expression - radiation effects; Gene Expression Regulation - immunology; Germinal Center - cytology; Humans; Immunoglobulin Class Switching - physiology; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - metabolism; Metformin - pharmacology; Mice; Mice, Knockout; Phosphorylation - drug effects; Phosphorylation - radiation effects; Plasma Cells - cytology; Plasma Cells - immunology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; Signal Transduction - radiation effects; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Proteins - antagonists & inhibitors; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2010.08.019

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. [Display omitted] ► CREB coactivator CRTC2 is inactivated by DNA breaks via ATM and LKB1 signaling ► CRTC2 inactivation is from AID-induced DNA breaks in germinal center B cells ► CRTC2 regulates proliferation, plasma cell differentiation, and lymphomagenic genes ► Failed CRTC2 inactivation is from defective AID→ATM→LKB1→AMPK→CRTC2 pathway signaling