title: AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling.
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.
authors.affiliation: Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Mara H
authors.initials: MH
authors.lastname: Sherman
authors.forename: Ali I
authors.initials: AI
authors.lastname: Kuraishy
authors.forename: Chetan
authors.initials: C
authors.lastname: Deshpande
authors.forename: Jason S
authors.initials: JS
authors.lastname: Hong
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Cacalano
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gatti
authors.forename: John P
authors.initials: JP
authors.lastname: Manis
authors.forename: Michael A
authors.initials: MA
authors.lastname: Damore
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Michael A
authors.initials: MA
authors.lastname: Teitell
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000528:radiation effects; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology* / Q000528:radiation effects; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000276:immunology* / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000276:immunology; D018858:Germinal Center / Q000166:cytology; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C493245:CRTC2 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D008687:Metformin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase