The ataxia telangiectasia mutated and cyclin D3 proteins cooperate to help enforce TCR? and IgH allelic exclusion.

ABSTRACT: 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? loci, ATM inhibits RAG expression and suppresses further V?-to-J? rearrangements to enforce Ig? allelic exclusion. Because V recombination between alleles is more strictly regulated for TCR? and IgH loci, we evaluated the ability of ATM to restrict biallelic expression and V-to-DJ recombination of TCR? and IgH genes. We detected greater frequencies of lymphocytes with biallelic expression or aberrant V-to-DJ rearrangement of TCR? or IgH loci in mice lacking ATM. A preassembled DJ? complex that decreases the number of TCR? rearrangements needed for a productive TCR? gene further increased frequencies of ATM-deficient cells with biallelic TCR? expression. IgH and TCR? proteins drive proliferation of prolymphocytes through cyclin D3 (Ccnd3), which also inhibits VH transcription. We show that inactivation of Ccnd3 leads to increased frequencies of lymphocytes with biallelic expression of IgH or TCR? genes. We also show that Ccnd3 inactivation cooperates with ATM deficiency to increase the frequencies of cells with biallelic TCR? 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? allelic exclusion and indicate that control of V-to-DJ rearrangements between alleles is important to maintain genomic stability.

SUBMITTER: Steinel NC 

PROVIDER: S-EPMC4157102 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature