DNA Double-Strand Breaks in Immunoglobulin Genes Undergoing Somatic Hypermutation

Bross, Linda; Fukita, Yosho; McBlane, Fraser; Démollière, Corinne; Rajewsky, Klaus; Jacobs, Heinz

doi:10.1016/s1074-7613(00)00059-5

Cited by 170 publications

(132 citation statements)

References 41 publications

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“…As both processes are associated with the occurrence of singleand double-stranded DNA breaks, it is presumed that they predispose to chromosomal translocations. [28][29][30][31][32][33] Indeed, translocations involving IgH S region sequences, likely owing to erroneous CSR have been found, for example, BCL-6 in FL and in diffuse large B-cell lymphoma (DLBCL), 34,35 C-MYC in sporadic Burkitt's lymphoma (BL) and in DLBCL 36 and Cyclin-D1, Cyclin-D3, FGFR3-MMSET and C-MAF in multiple myeloma. 37 Interestingly, a recent study on IgH S region breakpoints in t(3;14)(q27;q32) (BCL-6/IgH) demonstrated that in FL most IgH breakpoints involved Sg, whereas in DLBCL mostly Sm regions are involved.…”

Section: Somatic Ig Gene Alterations and Lymphomagenesismentioning

confidence: 99%

Molecular pathways in follicular lymphoma

2006

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Follicular lymphoma (FL) is one of the most common B-cell non-Hodgkin's lymphomas. The initiating genetic event found in B90% of FL is the t(14;18), causing constitutive expression of the antiapoptotic BCL-2 protein. The exact secondary alterations leading to full FL development are still poorly defined. In this review, we address (i) the genetic pathways associated with tumorigenesis and progression of FL, (ii) the role of micro-environmental factors with emphasis on B-cell receptor ligands and (iii) lymphoma models in mice and what they teach us about lymphomagenesis in man.

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Section: Somatic Ig Gene Alterations and Lymphomagenesismentioning

confidence: 99%

Molecular pathways in follicular lymphoma

2006

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“…The scattered DSB are processed into blunt DSB, possibly by the components of the mismatch repair system (MMR) [Bross et al, 2000;Kong and Maizels, 2001;Papavasiliou and Schatz, 2000;Stavnezer and Schrader, 2005]. During SHM, both single-stranded DNA (ssDNA) breaks and DSB are scattered along the target V sequence.…”

Section: Dna Cleavagementioning

confidence: 99%

Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants

et al. 2006

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For the Immunogenetics Special IssueActivation-induced cytidine deaminase (AID; gene symbol AICDA) is the key molecule required to induce immunoglobulin (Ig) class switch recombination (CSR) and somatic hypermutation (SHM) of the variable regions of Ig genes. Its deficiency causes a form of hyper-IgM (HIGM) syndrome. The study of natural AID mutants associated with HIGM as well as engineered mutants led to the characterization of the active domains of the protein. AID, through its cytidine deaminase activity, induces a targeted DNA lesion as an early step required for both CSR and SHM. Besides its cytidine deaminase activity, AID plays a further essential role in CSR, likely by recruiting CSR-specific cofactors by its C-terminus. A similar binding of SHM-specific cofactors to the N-terminal part is suggested by the functional characteristics of N ter AID artificial mutants. These data require confirmation in vivo. Finally, AID acts as a homo-, di-, or multimeric complex. Together, these data strongly suggest that AID, a master molecule for antibody diversification, exerts its activity on CSR not only as a cytidine deaminase enzyme but also as a docking protein, recruiting specific cofactors to a multimeric complex.

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“…Although it is still unclear whether DSB is an intermediate or a byproduct of SHM, DSB of target DNA associates with SHM reaction (34)(35)(36)(37). To determine whether ␥-H2AX focus formation on the IgH gene is detectable in OHT-treated BL2-⌬C-AIDER, we performed the ChIP assay with anti ␥-H2AX antibodies.…”

Section: Aid-dependent ␥-H2ax Focus Formation On Ig Genes In Shm-indumentioning

confidence: 99%

“…Since a causal role of DNA cleavage in SHM had first been proposed by Brenner and Milstein (38), a large number of investigators have reported the coincidence of DNA cleavage with SHM (34)(35)(36)(37)39). However, the direct requirement of DNA cleavage for SHM was not clearly demonstrated.…”

Section: Aid-dependent ␥-H2ax Focus Formation On Ig Genes In Shm-indumentioning

confidence: 99%

DNA cleavage in immunoglobulin somatic hypermutation depends onde novoprotein synthesis but not on uracil DNA glycosylase

Nagaoka

Ito

Muramatsu

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Activation-induced cytidine deaminase (AID) is required for the DNA cleavage step of Ig somatic hypermutation (SHM). However, its molecular mechanism is controversial. The RNA editing hypothesis postulates that AID deaminates cytosine in an unknown mRNA to generate a new mRNA encoding SHM endonuclease. On the other hand, the DNA deamination hypothesis explains DNA cleavage by cytosine deamination in DNA, followed by uracil removal by uracil DNA glycosylase (UNG). By using the protein synthesis inhibitor cycloheximide, we showed that SHM requires de novo protein synthesis in accord with predictions by the RNA editing hypothesis. In addition, we found that cycloheximide but not Ugi (the specific inhibitor of UNG) inhibited AID-dependent DNA cleavage in the Ig gene during SHM, by using histone H2AX focus formation as a marker of DNA cleavage. The results indicate the following order of events: AID expression, protein synthesis, DNA cleavage, and SHM. The requirement of protein synthesis but not of UNG for the DNA cleavage step of SHM forces us to reconsider the DNA deamination hypothesis and strengthens the RNA editing hypothesis.A ntigen stimulation induces three types of genetic alterations, namely somatic hypermutation (SHM), gene conversion (GC), and class switch recombination (CSR) in activated B cells, giving rise to antigen-specific Ig with high affinity and appropriate effector functions. SHM introduces point mutations in variable-region (V) genes without template, whereas GC does so with pseudo-V genes as template. When SHM and GC are coupled with selection by limited amounts of antigen, highaffinity antibody-producing B cells are enriched. CSR is a genetic process that switches Ig isotypes from IgM to other isotypes such as IgG and IgE, adding diverse effector functions to Ig with a given antigen specificity (1, 2).Activation-induced cytidine deaminase (AID), which is strictly expressed in activated B cells, especially in the germinal centers of lymphoid follicles, is essential for all three types of DNA alteration in B cells activated by antigen stimulation (3-6). AID has the strongest homology with apolipoprotein B mRNA editing catalytic subunit 1 (APOBEC-1) (reviewed in ref. 7). The genetic loci for AID and APOBEC-1 are tightly linked on mouse and human chromosomes (2). In addition to these evolutionary conservations, AID has functional similarities with APOBEC-1, including dimer formation, requirement of cofactors, and shuttling between cytoplasm and nucleus by N-terminal nuclear localization and C-terminal nuclear export domains (8-10).Evolutionary conservation and biochemical similarities between AID and apolipoprotein B mRNA editing catalytic subunit 1 (APOBEC-1) led us to propose the RNA editing hypothesis that AID converts unknown mRNA precursors to novel mRNAs encoding putative endonucleases to cleave target DNA (1). The alternative hypothesis (DNA deamination) explains DNA cleavage by direct deamination of cytosine (C) to uracil (U) in target DNA by AID. To generate strand breakage, U should be...

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DNA Double-Strand Breaks in Immunoglobulin Genes Undergoing Somatic Hypermutation

Cited by 170 publications

References 41 publications

Molecular pathways in follicular lymphoma

Molecular pathways in follicular lymphoma

Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants

DNA cleavage in immunoglobulin somatic hypermutation depends onde novoprotein synthesis but not on uracil DNA glycosylase

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