The Ataxia Telangiectasia Mutated and Cyclin D3 Proteins Cooperate To Help Enforce TCRβ and IgH Allelic Exclusion

Coordination of V rearrangements between loci on homologous chromosomes is critical for Ig and TCR allelic exclusion. The Ataxia Telangietasia mutated (ATM) protein kinase promotes DNA repair and activates checkpoints to suppress aberrant Ig and TCR rearrangements. In response to RAG cleavage of Ig kappa loci, ATM inhibits RAG expression and suppresses further V kappa-to-J kappa rearrangements to enforce Igk allelic exclusion. Because V recombination between alleles is more strictly regulated for TCR beta and IgH loci, we evaluated the ability of ATM to restrict biallelic expression and V-to-DJ recombination of TCR beta and IgH genes. We detected greater frequencies of lymphocytes with biallelic expression or aberrant V-to-DJ rearrangement of TCR beta or IgH loci in mice lacking ATM. A preassembled DJ beta complex that decreases the number of TCR beta rearrangements needed for a productive TCR beta gene further increased frequencies of ATM-deficient cells with biallelic TCR beta expression. IgH and TCR beta proteins drive proliferation of prolymphocytes through cyclin D3 (Ccnd3), which also inhibits V-H transcription. We show that inactivation of Ccnd3 leads to increased frequencies of lymphocytes with biallelic expression of IgH or TCR beta genes. We also show that Ccnd3 inactivation cooperates with ATM deficiency to increase the frequencies of cells with biallelic TCR beta or IgH expression while decreasing the frequency of ATM-deficient lymphocytes with aberrant V-to-DJ recombination. Our data demonstrate that core components of the DNA damage response and cell cycle machinery cooperate to help enforce IgH and TCR beta allelic exclusion and indicate that control of V-to-DJ rearrangements between alleles is important to maintain genomic stability.