Assembled DJ beta complexes influence TCR beta chain selection and peripheral V beta repertoire.

TCRbeta chain repertoire of peripheral alphabeta T cells is generated through the stepwise assembly and subsequent selection of TCRbeta V region exons during thymocyte development. To evaluate the influence of a two-step recombination process on Vbeta rearrangement and selection, we generated mice with a preassembled Dbeta1Jbeta1.1 complex on the Jbeta1(omega) allele, an endogenous TCRbeta allele that lacks the Dbeta2-Jbeta2 cluster, creating the Jbeta1(DJbeta) allele.

Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication.

Deregulation of cyclin D1 occurs in numerous human cancers through mutations, alternative splicing, and gene amplification. Although cancer-derived cyclin D1 mutants are potent oncogenes in vitro and in vivo, the mechanisms whereby they contribute to neoplasia are poorly understood. We now provide evidence derived from both mouse models and human cancer-derived cells revealing that nuclear accumulation of catalytically active mutant cyclin D1/CDK4 complexes triggers DNA rereplication, resulting from Cdt1 stabilization, which in turn triggers the DNA damage checkpoint and p53-dependent apoptosis.

ATM stabilizes DNA double-strand-break complexes during V(D)J recombination.

The ATM (ataxia-telangiectasia mutated) protein kinase mediates early cellular responses to DNA double-strand breaks (DSBs) generated during metabolic processes or by DNA-damaging agents. ATM deficiency leads to ataxia-telangiectasia, a disease marked by lymphopenia, genomic instability and an increased predisposition to lymphoid malignancies with chromosomal translocations involving lymphocyte antigen receptor loci. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs.