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
Source: PubMed

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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    • "There are increasing numbers of reports indicating that the ability of the DNA damage response cascade to modulate cell cycle progression can be used during developmental processes. Some of these processes were linked with limited DNA damage as happens in B cell differentiation (Sherman et al., 2010) or even in the absence of apparent DNA damage, such as in the midblastula transition in Drosophila melanogaster embryos (Sibon et al., 1997) or in the asynchronous division at two-cell-stage Caenorhabditis elegans embryos (Brauchle et al., 2003). The surprising finding that a regulatory cascade involved in DNA damage responses plays a role in a fungal developmental process mirrors these previous results and reinforces the emerging idea that checkpoint cascades may have roles beyond cell surveillance by virtue of their ability to interact with cell cycle machinery. "
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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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