DNA damage responses and suppression of chromosomal translocations in developing lymphocytes

Proper repair of DNA double stranded breaks (DSBs) is essential for cellular viability, maintenance of genomic stability, and suppression of malignant transformation. Antigen receptor genes are assembled in G1 phase lymphocytes by RAG/AID-initiated genomic recombination, which can lead to lymphomas with translocations generated through the mis-repair of RAG/AID induced DSBs. Cyclin D3 is uniquely expressed in lymphocytes during the proliferation bursts after V(D)J recombination and during class switch recombination. Here I show that cyclin D3 protein and mRNA, but not cyclin D2 protein, are lost in response to DSBs in developing B lymphocytes. The unique expression profile of cyclin D3 suggests that this response may be important for genomic stability during lymphocyte development and an immune response. The regulation of cyclin D3 is both ATM and p53 dependent, suggesting a role for p53 in cell cycle progression before the G1/S checkpoint. The p53 tumor suppressor inhibits persistence of RAG-generated DNA DSBs throughout the cell cycle and protects B cells from AID-initiated IgH/c-MYC translocations. Yet, germline p53-deficient (p53-/-) mice succumb to thymic lymphomas lacking T cell receptor (TCR) translocations and only develop B lymphoid tumors containing IgH translocations upon inactivation of DSB repair factors or AID over-expression. As a means to determine whether p53-/- thymic lymphomas can mask the outgrowth of B lineage lymphomas with IgH translocations, I generated Mb1 Cre:p53flox/flox mice with conditional p53 deletion in developing B cells. Mice survived tumor-free between 81-177 days with a median age of mortality at 128 days. MB1-cre:p53flox/flox tumors harbored clonal translocations, including IgH/c-MYC or other oncogenic translocations previously shown to be generated by RAG/AID initiated DSBs. My data reveal that the somatic inactivation of p53 in B lineage cells is sufficient to predispose mice to lymphomas that develop clonal translocations involving the aberrant repair of physiologic DSBs. My thesis projects have investigated the regulation of G1 phase following DNA damage in developing lymphocytes and the role of p53 in suppression of lymphomagenesis