Circular DNA is excised by immunoglobulin class switch recombination

Iwasato, Takuji; Shimizu, Akira; Honjo, Tasuku; Yamagishi, Hideo

doi:10.1016/0092-8674(90)90248-d

Cited by 239 publications

(125 citation statements)

References 27 publications

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“…Such DSBs might have several fates: They may be re-ligated, joined to another DSB in the same S region, or (for Sμ) joined to a DSB in a downstream S region to effect CSR (7). Rejoining DSBs within an S region, accompanied by resection or joining two DSBs within an S region, can cause internal switch deletions (ISDs), which often are large enough to be observed via Southern blotting (1,(8)(9)(10)(11). Large ISDs typically are assayed by activating B cells in culture to switch to a particular C H and then generating hybridomas and assaying for ISD in IgM-producing hybridomas that have not undergone bona fide CSR (11,12).…”

mentioning

confidence: 99%

Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70

Boboilă

Janković

Yan

et al. 2010

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

169

170

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Class switch recombination (CSR) in B lymphocytes is initiated by introduction of multiple DNA double-strand breaks (DSBs) into switch (S) regions that flank immunoglobulin heavy chain ( IgH ) constant region exons. CSR is completed by joining a DSB in the donor Sμ to a DSB in a downstream acceptor S region (e.g., Sγ1) by end-joining. In normal cells, many CSR junctions are mediated by classical nonhomologous end-joining (C-NHEJ), which employs the Ku70/80 complex for DSB recognition and XRCC4/DNA ligase 4 for ligation. Alternative end-joining (A-EJ) mediates CSR, at reduced levels, in the absence of C-NHEJ, even in combined absence of Ku70 and ligase 4, demonstrating an A-EJ pathway totally distinct from C-NHEJ. Multiple DSBs are introduced into Sμ during CSR, with some being rejoined or joined to each other to generate internal switch deletions (ISDs). In addition, S-region DSBs can be joined to other chromosomes to generate translocations, the level of which is increased by absence of a single C-NHEJ component (e.g., XRCC4). We asked whether ISD and S-region translocations occur in the complete absence of C-NHEJ (e.g., in Ku70/ligase 4 double-deficient B cells). We found, unexpectedly, that B-cell activation for CSR generates substantial ISD in both Sμ and Sγ1 and that ISD in both is greatly increased by the absence of C-NHEJ. IgH chromosomal translocations to the c-myc oncogene also are augmented in the combined absence of Ku70 and ligase 4. We discuss the implications of these findings for A-EJ in normal and abnormal DSB repair.

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mentioning

confidence: 99%

Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70

Boboilă

Janković

Yan

et al. 2010

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

169

170

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“…The evidence for DNA breaks in class-switch recombination is clear since the process involves the excision of intervening DNA between the upstream and downstream isotypes with the excised DNA detectable in the form of switch circles (Iwasato et al 1990;Matsuoka et al 1990;Von Schwedler et al 1990). The resolution of these breaks, necessary for the successful completion of switching, is dependent upon components of the DNA-dependent protein kinase (Casellas et al 1998;Manis et al 1998;Rolink et al 1996).…”

Section: Dna Breaks In Hypermutation and Isotype Switchingmentioning

confidence: 99%

In vivoandin vitrostudies of immunoglobulin gene somatic hypermutation

Sale

Bemark

Williams

et al. 2001

Phil. Trans. R. Soc. Lond. B

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Following antigen encounter, two distinct processes modify immunoglobulin genes. The variable region is diversi¢ed by somatic hypermutation while the constant region may be changed by class-switch recombination. Although both genetic events can occur concurrently within germinal centre B cells, there are examples of each occurring independently of the other. Here we compare the contributions of classswitch recombination and somatic hypermutation to the diversi¢cation of the serum immunoglobulin repertoire and review evidence that suggests that, despite clear di¡erences, the two processes may share some aspects of their mechanism in common.

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“…By means of CSR, the C m heavy chain of Ig is replaced by a different C x heavy chain, thus allowing the production of immunoglobulins of various isotypes with the same antigen affinity since the V region is left unchanged [Iwasato et al, 1990;Kinoshita and Honjo, 2000;Matsuoka et al, 1990]. Conversely, the SHM process modifies the antigen affinity (but not the isotype) of an antibody by introducing mutations in the V region at a very high frequency (1 Â 10 -3 bases per generation) [Jacobs et al, 2001;Storb et al, 1998].…”

Section: Introductionmentioning

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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Circular DNA is excised by immunoglobulin class switch recombination

Cited by 239 publications

References 27 publications

Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70

Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70

In vivoandin vitrostudies of immunoglobulin gene somatic hypermutation

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

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