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

Mara Sherman, Ali I. Kuraishy, Chetan Deshpande, Jason S. Hong, Nicholas A. Cacalano, Richard A. Gatti, John P. Manis, Michael A. Damore, Matteo Pellegrini, Michael A. Teitell

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)873-885
Number of pages13
JournalMolecular Cell
Volume39
Issue number6
DOIs
StatePublished - Sep 2010
Externally publishedYes

Fingerprint

Germinal Center
DNA Damage
Cell Differentiation
B-Lymphocytes
Cell Proliferation
Immunoglobulin Genes
DNA Breaks
B-Cell Lymphoma
Plasma Cells
AICDA (activation-induced cytidine deaminase)
Genome
Antibodies
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Sherman, M., Kuraishy, A. I., Deshpande, C., Hong, J. S., Cacalano, N. A., Gatti, R. A., ... Teitell, M. A. (2010). AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling. Molecular Cell, 39(6), 873-885. https://doi.org/10.1016/j.molcel.2010.08.019

AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling. / Sherman, Mara; 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.

In: Molecular Cell, Vol. 39, No. 6, 09.2010, p. 873-885.

Research output: Contribution to journalArticle

Sherman, M, Kuraishy, AI, Deshpande, C, Hong, JS, Cacalano, NA, Gatti, RA, Manis, JP, Damore, MA, Pellegrini, M & Teitell, MA 2010, 'AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling', Molecular Cell, vol. 39, no. 6, pp. 873-885. https://doi.org/10.1016/j.molcel.2010.08.019
Sherman, Mara ; 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. / AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling. In: Molecular Cell. 2010 ; Vol. 39, No. 6. pp. 873-885.
@article{ee3c75e483f94aefa1f6fa69a11326ad,
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.",
author = "Mara Sherman and Kuraishy, {Ali I.} and Chetan Deshpande and Hong, {Jason S.} and Cacalano, {Nicholas A.} and Gatti, {Richard A.} and Manis, {John P.} and Damore, {Michael A.} and Matteo Pellegrini and Teitell, {Michael A.}",
year = "2010",
month = "9",
doi = "10.1016/j.molcel.2010.08.019",
language = "English (US)",
volume = "39",
pages = "873--885",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling

AU - Sherman, Mara

AU - Kuraishy, Ali I.

AU - Deshpande, Chetan

AU - Hong, Jason S.

AU - Cacalano, Nicholas A.

AU - Gatti, Richard A.

AU - Manis, John P.

AU - Damore, Michael A.

AU - Pellegrini, Matteo

AU - Teitell, Michael A.

PY - 2010/9

Y1 - 2010/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77956915114&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956915114&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2010.08.019

DO - 10.1016/j.molcel.2010.08.019

M3 - Article

C2 - 20864035

AN - SCOPUS:77956915114

VL - 39

SP - 873

EP - 885

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 6

ER -