TY - JOUR
T1 - ADAR1 is vital for B cell lineage development in the mouse bone marrow
AU - Marcu-Malina, Victoria
AU - Goldberg, Sanja
AU - Vax, Einav
AU - Amariglio, Ninette
AU - Goldstein, Itamar
AU - Rechavi, Gideon
PY - 2016/8/23
Y1 - 2016/8/23
N2 - Adenosine deaminase acting on RNA (ADAR) 1 is the master editor of the transcriptome, catalyzing the conversion of adenosine to inosine (A-to-I). RNA transcripts fold into a variety of secondary structures including long intramolecular RNA duplexes that are the major substrate of ADAR1. Most A-to-I editing sites occur within RNA duplexes formed by complementary pairing of inverted retrotransposable elements interspersed within noncoding regions of transcripts. This catalytic activity of ADAR1 most likely prevents the abnormal activation of cytosolic nucleic acid sensors by self-dsRNAs. Homozygous disruption of mouse Adar is embryonic lethal due to a toxic type-I interferons response and correspondingly biallelic missense mutations in human ADAR1 cause a severe congenital interferonopathy. Here, we report that Cd19-Cre-mediated Adar gene ablation in the mouse causes a significant defect in the final stages of B cell development with an almost complete absence of newly formed immature and CD23+ mature recirculating B cells in the BM. Adar ablation in pre-B cells induced upregulation of typical interferon-stimulated genes (ISGs) and apoptosis upon further maturation. ADAR1 deficiency also inhibited the in vitro, IL-7-mediated, differentiation of BM-derived B cell precursors. In summary, ADAR1 is required, nonredundantly, for normal B lymphopoiesis in the BM and peripheral maintenance.
AB - Adenosine deaminase acting on RNA (ADAR) 1 is the master editor of the transcriptome, catalyzing the conversion of adenosine to inosine (A-to-I). RNA transcripts fold into a variety of secondary structures including long intramolecular RNA duplexes that are the major substrate of ADAR1. Most A-to-I editing sites occur within RNA duplexes formed by complementary pairing of inverted retrotransposable elements interspersed within noncoding regions of transcripts. This catalytic activity of ADAR1 most likely prevents the abnormal activation of cytosolic nucleic acid sensors by self-dsRNAs. Homozygous disruption of mouse Adar is embryonic lethal due to a toxic type-I interferons response and correspondingly biallelic missense mutations in human ADAR1 cause a severe congenital interferonopathy. Here, we report that Cd19-Cre-mediated Adar gene ablation in the mouse causes a significant defect in the final stages of B cell development with an almost complete absence of newly formed immature and CD23+ mature recirculating B cells in the BM. Adar ablation in pre-B cells induced upregulation of typical interferon-stimulated genes (ISGs) and apoptosis upon further maturation. ADAR1 deficiency also inhibited the in vitro, IL-7-mediated, differentiation of BM-derived B cell precursors. In summary, ADAR1 is required, nonredundantly, for normal B lymphopoiesis in the BM and peripheral maintenance.
KW - ADAR1
KW - B cell
KW - Epitranscriptomics
KW - Lymphopoiesis
KW - RNA editing
UR - http://www.scopus.com/inward/record.url?scp=84983503853&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.11029
DO - 10.18632/oncotarget.11029
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C2 - 27494846
AN - SCOPUS:84983503853
SN - 1949-2553
VL - 7
SP - 54370
EP - 54379
JO - Oncotarget
JF - Oncotarget
IS - 34
ER -