The recombination activating gene (RAG) is a lymphoid-specific endonuclease involved in the V(D)J recombination It has long been proposed that rills-targeting of RAG proteins is one of the factors contributing to lymphoid chromosomal translocation bearing authentic recombination signal sequences (RSSs) in immunoglobulin (Ig) and T cell receptor (TCR) gene loci or cryptic RSSs (cRSSs) However it is unclear whether primary sequence-dependent targeting mistake Involved in the chromosomal translocation bearing no Ig/TCR gene loci is mediated by RAG proteins Using an extrachromosomal recombination assay we found RAG-dependent recombination in the regions dense in breakpoints within TEL and AML1 gene loci related to acute lymphoid leukemia-associated t(12 21)(p13 q22) chromosomal translocation Sequence analyses revealed several heptamer-like sequences located in the vicinity of RAG-dependent recombination sites By chromatin immunoprecipitation (ChIP) and ligation-mediated PCR (LM-PCR) assays we have shown that RAG proteins bind to and cleave the TEL translocation region dense in breakpoints These results suggest that mis-targeting of RAG proteins to cRSSs within TEL and AML1 translocation regions might be responsible for the t(12 21)(p13 q22) chromosomal translocation not bearing Ig/TCR regions (C) 2010 Elsevier Inc All rights reserved