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Mechanisms of human lymphoid chromosomal translocations

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From Nature Reviews Cancer

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Key Points

  • Neoplastic chromosomal translocations (and other pathological chromosomal rearrangements) can be considered in terms of a breakage phase, in which broken duplex DNA ends are generated, and then a rejoining phase. The rejoining phase is carried out by the non-homologous DNA end-joining (NHEJ) pathway.

  • In B lymphoid neoplasms, the breakage phase is often initiated by the activation-induced deaminase (AID) on the chromosome bearing the oncogene and the recombination activating gene (RAG) complex, comprised of RAG1 and RAG2, on the IgH chromosome. In T lymphoid neoplasms, the RAG complex is often responsible for the DNA breakage phase on both chromosomes.

  • For B lymphoid neoplasms, the chromosome break sites are often in hot spots, and the breaks are often near CG (that is, CpG sites) or WGCW (where W = A or T) motifs, which are sites at which AID can initiate lesions that lead to double-strand DNA breaks. AID is known to deaminate only cytosines that are within single-stranded DNA (ssDNA) regions.

  • The ssDNA in the hot spots may have various causes, which are still under investigation, such as transcriptionally induced topological tension, R-loop formation or some type of strand slippage at short repeat sequences. Concurrent expression of a low level of AID in pre-B cells, along with the usual high expression level of the RAG complex, permits translocation events in human cells in which a RAG-generated break is joined to an AID-initiated break.

  • Examples of RAG–AID-induced translocations in humans include t(14;18) translocation involving the immunoglobulin heavy (IGH) locus and the BCL2 gene. The t(11;14) translocation involving the IGH locus and the BCL1 locus (which is close to the cyclin D1 (CCND1) gene) is another example of a translocation that occurs in human lymphomas.

  • The principles discerned from lymphoid translocations are useful for considering the mechanism of chromosomal rearrangements and translocations generally. In particular, sequence motif analysis may be generally useful for assessing translocations in non-lymphoid cancer cells.

Abstract

Analysis of chromosomal translocation sequence locations in human lymphomas has provided valuable clues about the mechanism of the translocations and when they occur. Biochemical analyses on the mechanisms of DNA breakage and rejoining permit formulation of detailed models of the human chromosomal translocation process in lymphoid neoplasms. Most human lymphomas are derived from B cells in which a DNA break at an oncogene is initiated by activation-induced deaminase (AID). The partner locus in many cases is located at one of the antigen receptor loci, and this break is generated by the recombination activating gene (RAG) complex or by AID. After breakage, the joining process typically occurs by non-homologous DNA end-joining (NHEJ). Some of the insights into this mechanism also apply to translocations that occur in non-lymphoid neoplasms.

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Figure 1: Causes and repair of double-strand DNA breaks.
Figure 2: Common chromosomal translocations in T and B cells.
Figure 3: A high proportion of breakpoints on BCL2, BCL1 and E2A fall into fragile regions that are smaller than 600 bp.
Figure 4: Timing of chromosomal translocations as a function of B-cell development.
Figure 5: Fraction of human haematopoietic malignancies explained by AID-type breaks.

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Acknowledgements

The author thanks R. Mosteller and I. Siddiqi for comments on the manuscript. Work in the author's laboratory is supported by the US National Institutes of Health (NIH). Many collaborators as well as members of the Lieber laboratory were central to the work leading to this review. Z. Lu compiled the information leading to Figure 5.

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  1. USC Norris Comprehensive Cancer Center, Room 5428, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, MC9176, Los Angeles, 90089-9176, California, USA

    Michael R. Lieber

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Correspondence to Michael R. Lieber.

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Supplementary information

41568_2016_BFnrc201640_MOESM263_ESM.pdf

Supplementary information S1 (figure) | Loading of Enzymatic Activities at the Two DNA Ends in the Nonhomologous DNA End Joining Pathway. (PDF 156 kb)

Supplementary information S2 (figure) | Resection of the Two DNA Ends at a DSB Prior to NHEJ. (PDF 236 kb)

Supplementary information S3 (figure) | Developmental Expression of RAG and AID. (PDF 106 kb)

Supplementary information S4 (figure) | Diagram of the c-MYC Translocation. (PDF 155 kb)

41568_2016_BFnrc201640_MOESM267_ESM.pdf

Supplementary information S5 (figure) | CG and GC Pack C's Across from One Another in a DNA Duplex Making These Sites Vulnerable to Double-Strand Breakage. (PDF 131 kb)

Supplementary information S6 (figure) | Three Mechanisms for Generating AID-Type Double-Strand Breaks. (PDF 127 kb)

Supplementary information S7 (figure) | BCL-6 translocation breakpoints in human B-cell lymphomas. (PDF 178 kb)

Glossary

Lymphoid neoplasms

Malignancies of B or T cells. If the malignant cells are primarily in the spleen, lymph nodes or other peripheral lymphoid tissues, they are lymphomas. If the malignant cells are primarily in the blood and bone marrow, they are called lymphoid leukaemias. Acute lymphoblastic leukaemia (ALL) can be considered both a lymphoma and a leukaemia in humans.

Activation-induced deaminase

(AID). A cytidine deaminase that converts C to T (or methyl-C to U) in B cells of all vertebrates when it is expressed (predominantly in germinal centres, but at low levels in pre-B cells). AID is not expressed in T cells.

Recombination activating gene (RAG) complex

Antigen receptors of the vertebrate immune system rely on RAG1 and RAG2, which form the RAG complex, which creates double-strand DNA breaks at specific sequences called recombination signal sequences (RSSs).

Reciprocal translocations

These are stable only if each derivative chromosome has one centromere; otherwise, one chromosome is lost due to lack of a centromere, and the other chromosome suffers repeated breakage–fusion–bridge cycles.

Non-homologous DNA end-joining

(NHEJ). Major pathway for repairing double-strand DNA breaks that do not have homology between them (although shared microhomology of 1–3 bp between the two DNA ends is often used during the joining process).

V(D)J recombination

The DNA recombination process in pro-B, pre-B, pro-T and pre-T cells by which the variable domain exons of antigen receptors are assembled from subexonic segments called V, D and J to generate a complete T cell receptor or immunoglobulin gene.

Alternative DNA end-joining

(a-EJ, alt-EJ, alt-NHEJ or a-NHEJ). Classical or canonical NHEJ (c-NHEJ) can have a few nucleotides of microhomology (usually 0–3 bp). Longer regions of microhomology (for example, >3 bp) are joined in a manner that is less reliant on most of the NHEJ factors, and any ligase (ligase 1, 3 or 4) will suffice. Whether a-EJ is a separate pathway or simply substitution of ligase 1 or 3 for ligase 4 in the joining of ends that anneal well due to >3 bp of terminal homology is not yet certain.

DNA nick

Within duplex DNA, a break in the phosphodiester backbone of one strand but not the other is called a nick. A ligatable nick has a 5′-phosphate and a 3′OH.

Fragile sites

Some regions of DNA in the human genome are 10- to 1,000-fold more likely to be a site of breakage or trans- location. The fragile sites or zones in this Review occur in otherwise normal patients and these fragile sites or zones are 20–2,000 bp in length. These naturally occurring sites are to be distinguished from the fragile sites or FRA sites that can be induced by DNA polymerase chain terminators or poisons such as hydroxyurea, because these are 300,000 to 10,000,000 bp in length.

Immunoglobulin heavy (IGH) locus class switch recombination

The DNA recombination process by which the heavy chain isotype is changed from making IgM to making IgG, IgA or IgE.

V, D or J segments

Portions of a complete variable domain exon. I call these subexons. The V, D and J segments have recombination signal sequences (RSSs) located next to them to enable the recombination activating gene (RAG) complex to bind and cut to initiate the V(D)J recombination process.

Recombination signal sequence

(RSS). RSSs are the targeting sequences next to V, D and J segments for RAG complex binding; an RSS consists of a palindromic heptamer (CACAGTG) and an AT-rich nonamer (ACAAAAACA) separated by 12 or 23 bp.

Germinal centres

When B cells in the peripheral lymphoid tissues (for example, lymph node, spleen or Peyer's patches) proliferate in response to a specific antigen or antigenic hapten, then a sphere of cells results that is surrounded by B and T cells. These spheres or balls of B cells are called germinal centres. Activation-induced deaminase (AID) levels are high in the B cells within a germinal centre, resulting in immunoglobulin heavy chain class switch recombination and somatic hypermutation.

Peyer's patches

Gut-associated lymphoid tissue (GALT) within the ileum of the small intestine, which can form germinal centres.

Minichromosomes

In experimental systems, stable replicating plasmids are called minichromosomes. In human cells, Epstein–Barr virus (EBV) or simian virus 40 (SV40) origins of replication can drive replication of these minichromosomes with the help of the EBNA1 protein or SV40 large T antigen helicase, respectively. In mouse or rat cells, the polyoma virus origin of replication can serve this purpose, with the support of the polyoma large T antigen helicase.

Pseudo-RSS

A sequence that is similar to a recombination signal sequence (RSS), in having sequences that bear some similarity to the RSS heptamer and nonamer. A pseudo-RSS is not adjacent to a V, D or J segment, and thus has no function. But the RAG complex can cut at a pseudo-RSS to cause a deletion or translocation.

R-loop

Sequences that are G-rich on the non-template strand generate a corresponding G-rich RNA that can anneal back to the template strand while the RNA polymerase is still transcribing. This can result in long R-loops of lengths up to >1 kb. Documented R-loops at the immunoglobulin heavy locus (IGH) switch regions have been demonstrated by functional assays, by chemical probing using bisulfite and by immunoprecipitation using an antibody (S9.6 antibody after RNase A treatment to remove free RNA).

Divergently directed transcription

Two promoters can be close to one another and directing transcription away from one another. Approximately 10–20% of the human genome has divergently directed promoters, depending on non-coding RNAs.

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Lieber, M. Mechanisms of human lymphoid chromosomal translocations. Nat Rev Cancer 16, 387–398 (2016). https://doi.org/10.1038/nrc.2016.40

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