Somatic Hypermutation in the Absence of DNA-Dependent Protein Kinase Catalytic Subunit (DNA-Pkcs) or Recombination-Activating Gene (Rag)1 Activity

Bemark, Mats; Sale, Julian E.; Kim, Hye-Jung; Berek, Claudia; Cosgrove, Ruth A.; Neuberger, Michael S.

doi:10.1084/jem.192.10.1509

Cited by 92 publications

(61 citation statements)

References 20 publications

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“…Significant levels of mutation are found solely in the translocated c-MYC allele and then only downstream of the promoter (¢gure 4) (Bemark & Neuberger 2000). Like immunoglobulin mutation in Ramos, the mutation in c-MYC was heavily biased towards G and C nucleotides (32:33 as opposed to a random expectation of 62% for this sequence) and, in particular, to AGC hot spots (52% as opposed to a randomly expected 18%).…”

Section: Hypermutation and Translocation: Hypermutation Of The Translmentioning

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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Section: Hypermutation and Translocation: Hypermutation Of The Translmentioning

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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“…The role of the phosphorylated histone gH2AX and the repair protein 53BP1 has been also demonstrated in CSR (but not SHM) in the corresponding knockout mice Sengupta et al, 2004]. The nonhomologous end-joining (NHEJ) DNA repair enzymes (including DNA-dependent protein Kinase [DNA-PK], and the KU proteins) [Casellas et al, 1998;Manis et al, 1998;Rolink et al, 1996] which join the S m and S x sequences are necessary for CSR but dispensable for SHM [Bemark et al, 2000;Cascalho et al, 1998;Evans and Alani, 2000;Kenter, 1999]. In contrast, SHM-induced DNA repair involves the MMR enzymes [Schrader et al, 1999] and the error-prone DNA polymerases Z, z, and y [Masuda et al, 2005;Zan et al, 2001;Zeng et al, 2001].…”

Section: Dna Repairmentioning

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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“…We propose that such lesions become associated with Nbs1/γ-H2AX foci in the G1 phase of the cell cycle and that repair proceeds by NHEJ [14][15][16] . By contrast, DNA breaks associated with hypermutation in V genes are found in the S/G2 phase of the cell cycle 11 and are repaired by pathways independent of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) 27 . The lesions in V genes can lead to either gene conversion or somatic hypermutation depending on the mechanism of DNA repair 28 .…”

mentioning

confidence: 99%

AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching

Petersen

Casellas

Reina‐San‐Martin

et al. 2001

Nature

462

438

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Class switch recombination (CSR) is a region-specific DNA recombination reaction that replaces one immunoglobulin heavy-chain constant region (CH) gene with another. This enables a single variable (V) region gene to be used in conjunction with different downstream CH genes, each having a unique biological activity. The molecular mechanisms that mediate CSR have not been defined, but activation-induced cytidine deaminase (AID), a putative RNA-editing enzyme, is required for this reaction 1 . Here we report that the Nijmegen breakage syndrome protein (Nbs1) and phosphorylated H2A histone family member X (γ-H2AX, also known as γ-H2afx), which facilitate DNA double-strand break (DSB) repair 2-4 , form nuclear foci at the CH region in the G1 phase of the cell cycle in cells undergoing CSR, and that switching is impaired in H2AX -/-mice. Localization of Nbs1 and γ-H2AX to the IgH locus during CSR is dependent on AID. In addition, AID is required for induction of switch region (Sμ)-specific DNA lesions that precede CSR. These results place AID function upstream of the DNA modifications that initiate CSR.Correspondence and requests for materials should be addressed to A.N. (andre_nussenzweig@nih.gov) or M.C.N. (nussen@mail.rockefeller.edu).. Supplementary Information accompanies the paper on Nature's website (http://www.nature.com). Competing interests statementThe authors declare that they have no competing financial interests. To determine whether DNA repair factors associate with DSBs at the switch regions, we first examined the intracellular localization of γ-H2AX, Nbs1, Rad51 and Brca1 in activated B cells by immunofluorescence. Brca1 and Rad51 are required for homologous recombination, the Mre11-Rad50-Nbs1 complex has been implicated in both homologous recombination and non-homologous end-joining (NHEJ), and γ-H2AX is critical for recruiting these repair factors to DSBs 6 and facilitates NHEJ in Saccharomyces cerevisiae 4 . All four proteins showed diffuse nuclear staining in most of the resting B cells from C57BL/6 wild-type mice. High local concentrations of these factors (nuclear foci) were detected in a very small percentage of cells (<5%), which increased significantly when the cells were stimulated to undergo CSR in vitro with lipopolysaccharide (LPS) and interleukin (IL)-4 (Fig. 1a). After 3 days of stimulation, 37% of the B cells contained discrete Brca1 foci (12 ± 6 per cell) and 43% contained Rad51 foci (7 ± 3 per cell), consistent with previous results 7 ; the remaining cells exhibited a weak, diffuse pattern of nuclear staining (Fig. 1a). Many of the stimulated B cells also formed Nbs1 foci (32% contained, on average, 3 ± 2 per cell) and γ-H2AX foci (40% contained, on average, 4.5 ± 3 per cell). To determine which of these repair factors are co-localized in activated B cells, we performed two colour immunofluoresence experiments (Fig. 1b). Only 20% of the cells that contained Rad51 and Nbs1 (n = 687) or Brca1 and Nbs1 foci (n = 431) exhibited co-localization. In contrast, γ-H2AX foci co-localiz...

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Somatic Hypermutation in the Absence of DNA-Dependent Protein Kinase Catalytic Subunit (DNA-Pkcs) or Recombination-Activating Gene (Rag)1 Activity

Cited by 92 publications

References 20 publications

In vivoandin vitrostudies of immunoglobulin gene somatic hypermutation

In vivoandin vitrostudies of immunoglobulin gene somatic hypermutation

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

AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching

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