Human Chromosomal Translocations at CpG Sites and a Theoretical Basis for Their Lineage and Stage Specificity

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2008.10.035 Byline: Albert G. Tsai (1), Haihui Lu (1), Sathees C. Raghavan (1), Markus Muschen (2), Chih-Lin Hsieh (1), Michael R. Lieber (1) Keywords: DNA; PROTEINS; HUMDISEASE Abstract: We have assembled, annotated, and analyzed a database of over 1700 breakpoints from the most common chromosomal rearrangements in human leukemias and lymphomas. Using this database, we show that although the CpG dinucleotide constitutes only 1% of the human genome, it accounts for 40%-70% of breakpoints at pro-B/pre-B stage translocation regions -- specifically, those near the bcl-2, bcl-1, and E2A genes. We do not observe CpG hotspots in rearrangements involving lymphoid-myeloid progenitors, mature B cells, or T cells. The stage specificity, lineage specificity, CpG targeting, and unique breakpoint distributions at these cluster regions may be explained by a lesion-specific double-strand breakage mechanism involving the RAG complex acting at AID-deaminated methyl-CpGs. Author Affiliation: (1) Norris Comprehensive Cancer Center, Room 5428, Departments of Pathology, Biochemistry and Molecular Biology, Molecular Microbiology and Immunology, Urology, and Biological Sciences, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, MC9176, Los Angeles, CA 90089-9176, USA (2) Departments of Pediatrics, and Biochemistry and Molecular Biology, University of Southern California Norris Comprehensive Cancer Center, Children's Hospital of Los Angeles, Los Angeles, CA 90027, USA Article History: Received 8 April 2008; Revised 29 July 2008; Accepted 21 October 2008 Article Note: (miscellaneous) Published: December 11, 2008