Coupling of V(D)J Recombination to the Cell Cycle Suppresses Genomic Instability and Lymphoid Tumorigenesis

Abstract

Summary V(D)J gene segment recombination is linked to the cell cycle by the periodic phosphorylation and destruction of the RAG-2 protein at the G1-to-S cell cycle transition. To examine the function of this coupling, we constructed mice in which the phosphorylation site at threonine 490 of RAG-2 was mutated to alanine. The RAG-2 T490A mutation uncoupled DNA cleavage from cell cycle and promoted aberrant recombination. Similar aberrant recombination products were observed in mice deficient in the Skp2 ubiquitin ligase subunit, which is required for periodic destruction of RAG-2. On a p53-deficient background the RAG-2 T490A mutation induced lymphoid malignancies characterized by clonal chromosomal translocations involving antigen receptor genes. Taken together these observations provide a direct link between the periodic destruction of RAG-2 and lymphoid tumorigenesis. We infer that cell cycle control of the V(D)J recombinase limits the potential genomic damage that could otherwise result from RAG-mediated DNA cleavage.

NF-κB and AKT signaling prevent DNA damage in transformed pre-B cells by suppressing RAG1/2 expression and activity

“…10 Consistent with this, our study shows that AKT and NF-kB inhibition leads to increased RAG-dependent DNA damage, most prominently in large cycling cells, which may provoke genomic instability. In agreement, our LM-PCR analysis confirms that RAG is active in S phase under these conditions.…”

“…8,9 A breach of this regulation results in genomic instability that activates a p53-dependent checkpoint, as was shown by the increased lymphomagenesis in p53-deficient RAG2-T490A mice. 10 There is ample evidence for the involvement of RAG in chromosomal aberrations in lymphomas and leukemias, which underscores the importance of proper regulation of this potentially harmful recombination mechanism. 11 Moreover, B-cell acute lymphoblastic leukemias (B-ALLs) show a developmental block at the pro-to pre-B cell stage and frequently display constitutive RAG, terminal deoxy-transferase (TdT) expression, and ongoing Ig gene recombinations.…”

Histone methylation and V(D)J recombination

“…This region also contains a phosphorylation site for cyclin A-Cdk2 at Thr490 and a PHD finger [31]. Thr490 and the interval spanning amino acids 499-508 are linked to the periodic destruction of RAG2 in G1-S transition by Skp1-Cul1-Skp2 (Skp2-SCF) dependent polyubiquitylation [32,33]. Since V(D)J recombination occurs in G1 phase, the destruction of RAG protein may function to prevent an aberrant RAG activity outside of G1.…”

Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling

“…The checkpoint also segregates the proliferation of pre-B cells from the recombination of immunoglobulin light chain loci. Failure to do so can result in genomic instability and neoplastic transformation 4 .…”