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. 2017 Aug 30;18(9):1876. doi: 10.3390/ijms18091876

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© 2017 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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DNA damage triggers an ATM- and phosphorylation-dependent S region DSB feedforward loop. Activation-induced cytidine deaminase (AID) instigates DNA double-strand breaks (DSBs) in the switch (S) regions upstream of each immunoglobulin (Ig) constant (C) region in the heavy chain locus (IgH). Activation of ataxia telangiectasia mutated (ATM) kinase by DSBs triggers the protein kinase A (PKA) -dependent phosphorylation of AID on serine 38 (represented by P in the black circle), which enhances the interaction of AID with apurinic/apyrimidinic endonuclease 1 (APE1), which is involved in processing of AID lesions into DSBs. ATM also regulates the synapsis of S regions required for intrachromosomal recombination; the order in which the S region DSBs occur; the recruitment of DNA repair factors necessary for resolvement of the recombination (indicated in the black frame). Simultaneously, ATM may trigger p53-dependent activation of apoptosis, which is counteracted by the B-cell lymphoma 6 (BCL6) protein. Arrows represent positive regulation (activation); T-bar represent negative regulation (inhibition).