Email updates

Keep up to date with the latest news and content from BMC Genomics and BioMed Central.

This article is part of the supplement: International Workshop on Computational Systems Biology: Approaches to Analysis of Genome Complexity and Regulatory Gene Networks

Open Access Highly Accessed Research

Mechanisms of chromosomal rearrangement in the human genome

Albert G Tsai and Michael R Lieber*

Author affiliations

USC Norris Comprehensive Cancer Ctr., Rm. 5428 Departments of Pathology, Biochemistry & Molecular Biology, Molecular Microbiology & Immunology, and of Biological Sciences (Section of Molecular & Computational Biology), University of Southern California 1441 Eastlake Ave., MC9176 Los Angeles, CA 90089-9176, USA

For all author emails, please log on.

Citation and License

BMC Genomics 2010, 11(Suppl 1):S1  doi:10.1186/1471-2164-11-S1-S1

Published: 10 February 2010

Abstract

Many human cancers are associated with characteristic chromosomal rearrangements, especially hematopoietic cancers such as leukemias and lymphomas. The first and most critical step in the rearrangement process is the induction of two DNA double-strand breaks (DSB). In all cases, at least one of the two DSBs is generated by a pathologic process, such as (1) randomly-positioned breaks due to ionizing radiation, free radical oxidative damage, or spontaneous hydrolysis; (2) breaks associated with topoisomerase inhibitor treatment; or (3) breaks at direct or inverted repeat sequences, mediated by unidentified strand breakage mechanisms. In lymphoid cells, one of the two requisite DSBs is often physiologic, the result of V(D)J recombination or class switch recombination (CSR) at the lymphoid antigen receptor loci. The RAG complex, which causes the DSBs in V(D)J recombination, can cause (4) sequence-specific, pathologic DSBs at sites that fit the consensus of their normal V(D)J recombination signal targets; or (5) structure-specific, pathologic DSBs at regions of single- to double-strand transition. CSR occurs specifically in the B-cell lineage, and requires (6) activation-induced cytidine deaminase (AID) action at sites of single-stranded DNA, which may occur pathologically outside of the normal target loci of class switch recombination regions and somatic hypermutation (SHM) zones. Recent work proposes a seventh mechanism: the sequential action of AID and the RAG complex at CpG sites provides a coherent model for the pathologic DSBs at some of the most common sites of translocation in human lymphoma – the bcl-2 gene in follicular lymphoma and diffuse large B-cell lymphoma, and the bcl-1 gene in mantle cell lymphoma.