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Expression and recruitment of uracil-DNA glycosylase are regulated by E2A during antibody diversification
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
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2014 (Engelska)Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 60, nr 1, s. 23-31Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

B-lymphocytes can modify their immunoglobulin (Ig) genes to generate specific antibodies with a new isotype and enhanced affinity against an antigen. Activation-induced cytidine deaminase (AID), which is positively regulated by the transcription factor E2A, is the key enzyme that initiates these processes by deaminating cytosine to uracil in Ig genes. Nuclear uracil-DNA glycosylase (UNG2) is subsequently required for uracil processing in the generation of high affinity antibodies of different isotypes. Here we show that the transcription factor E2A binds to the UNG2 promoter and represses UNG2 expression. Inhibition of E2A by binding of Ca2+-activated calmodulin alleviates this repression. Furthermore, we demonstrate that UNG2 preferentially accumulates in regions of the Ig heavy chain (IgH) gene containing AID hotspots. Calmodulin inhibition of E2A strongly enhances this UNG2 accumulation, indicating that it is negatively regulated by E2A as well. We show also that over-expression of E2A can suppress class switch recombination. The results suggest that E2A is a key factor in regulating the balance between AID and UNG2, both at expression and Ig targeting levels, to stimulate Ig diversification and suppress normal DNA repair processes. (c) 2014 Elsevier Ltd. All rights reserved.

Ort, förlag, år, upplaga, sidor
2014. Vol. 60, nr 1, s. 23-31
Nyckelord [en]
B cells, Cell differentiation, Antibodies, Gene regulation, Transcription factors
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-90404DOI: 10.1016/j.molimm.2014.03.011ISI: 000336473200004Scopus ID: 2-s2.0-84898920232OAI: oai:DiVA.org:umu-90404DiVA, id: diva2:733596
Tillgänglig från: 2014-07-10 Skapad: 2014-06-23 Senast uppdaterad: 2023-03-24Bibliografiskt granskad

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Wallenius, AndersHauser, JannekGrundström, Thomas

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Wallenius, AndersHauser, JannekGrundström, Thomas
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Institutionen för molekylärbiologi (Medicinska fakulteten)
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Molecular Immunology
Cell- och molekylärbiologi

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