Recent insights into the formation of RAG-Induced chromosomal translocations

Chromosomal translocations are found in many types oftumors, where they may be either a cause or a result of malignant transformation. In lymphoid neoplasms, however, it is clear that pathogenesis is initiated by any of a number ofrecurrent DNA rearrangements. These particular translocations typically place an oncogene under the regulatory control ofan Ig or TCR gene promoter, dysregulating cell growth, differentiation, or apoptosis. Given that physiological DNA rearrangements (V(D)J and class switch recombination) are integral to lymphocyte development, it is critical to understand how genomic stability is maintained during these processes. Recent advances in our understanding ofDNA damage signaling and repair have provided clues to the kinds ofmechanisms that lead to V(D)J-mediated translocations. In turn, investigations into the regulation of V(D)J joining have illuminated a formerly obscure pathway ofDNArepair known as alternative NHEJ, which is error-prone and frequently involved in translocations. In this chapter we consider recent advances in our understanding of the functions of the RAG proteins, RAG interactions with DNA repair pathways. damage Signaling and chromosome biology, all ofwhich shed light on how mistakes at different stages of V(D)J recombination might lead to leukemias and lymphomas. © 2009 Landes Bioscience and Springer Science+Business Media.