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

Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Molecular cell (Impact Factor: 14.46). 09/2010; 39(6):873-85. DOI: 10.1016/j.molcel.2010.08.019
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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.

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Available from: Michael A Damore, Aug 23, 2015
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    • "During CSR, production of DSBs requires the programmed formation of R-loops (Roy et al., 2008) and deoxycytidine deamination mediated by AID (Chaudhuri et al., 2007). The response to DSBs produced by AID activates an ATM-dependent signaling pathway that regulates a network of genes involved in proliferation, B-cell self-renewal, and cell differentiation (Sherman et al., 2010). Interestingly, unscheduled AID-mediated DSBs are implicated in cancer (Park, 2012) even though it is unclear if the link with cancer involves targeting of aberrant R-loop structures. "
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    • "In neurons, BDNF-induced activation of PKA in a single neurite outgrowth triggers localized phosphorylation of S428 (S431 in mice), which in this setting appears to stabilize the LKB1–STRAD–MO25 complex required for axon specification [44] [48]. During immunoglobulin gene remodeling DNA strand breaks induce ATM, which in this context leads to phosphorylation of LKB1, inactivation of CRTC2 (also known as TORC2) and differentiation of B cells [49], which suggests a mechanism where ATM phosphorylation of LKB1 on T366 [50], induces LKB1 to phosphorylate either SIK or AMPK, both capable of phosphorylating and inactivating CRTC2 [51]. In myocytes and adipocytes Fyn-mediated tyrosine phosphorylation on Y261 and Y365 of LKB1 decreases cytoplasmic LKB1 and AMPK T-loop phosphorylation [52]. "
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