Evolution of the Immunoglobulin Heavy Chain Class Switch Recombination Mechanism

Chaudhuri, Jayanta; Basu, Uttiya; Zarrin, Ali A.; Yan, Catherine T.; Franco, Sonia; Perlot, Thomas; Vuong, Bao Q.; Wang, Jing H.; Phan, Ryan T.; Datta, Abhishek; Manis, John P.; Alt, Frederick W.

doi:10.1016/s0065-2776(06)94006-1

Cited by 233 publications

(341 citation statements)

References 285 publications

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“…AID also initiates class switch recombination (CSR), which exchanges the exons encoding the Fc region of the antibody from the default IgM to another isotype 1,2 . All the known components in these pathways except for AID are ubiquitous DNA repair enzymes (reviewed in [3][4][5] ). Indeed, AID is able to trigger SHM and CSR in non-B cell models 6,7 and since such mutagenic and recombinogenic enzyme is potentially dangerous, it needs to be tightly regulated.…”

Section: Introductionmentioning

confidence: 99%

Active nuclear import and cytoplasmic retention of activation-induced deaminase

Patenaude

Orthwein

et al. 2009

Nat Struct Mol Biol

134

175

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The enzyme Activation Induced Deaminase (AID) triggers antibody diversification in B-cells by catalyzing deamination and consequently mutation of immunoglobulin genes. To minimize off-target deamination, AID is restrained by several regulatory mechanisms including nuclear exclusion, thought to be mediated exclusively by active nuclear export. Here we identify two other mechanisms involved in controlling AID subcellular localization. AID is unable to passively diffuse into the nucleus, despite its small size, its nuclear entry requiring active import mediated by a conformational nuclear localization sequence (NLS). We also identify a determinant for AID cytoplasmic retention in its Cterminus, which hampers diffusion to the nucleus, competes with nuclear import and is critical for maintaining the predominantly cytoplasmic localization of AID in steady-state conditions. Blocking nuclear import alters the balance between these processes in favor of cytoplasmic retention, resulting in reduced isotype class switching.3

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Section: Introductionmentioning

confidence: 99%

Active nuclear import and cytoplasmic retention of activation-induced deaminase

Patenaude

Orthwein

et al. 2009

Nat Struct Mol Biol

134

175

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“…Recent studies clearly demonstrated that Polη and Polζ are the major TLPs to introduce SHM (11,12). Although CSR is also initiated by AID-dependent SSB, CSR has several distinct features from SHM such as SSB processing to double strand break (DSB) and joining of appropriate pairs of DSB ends (13,14).…”

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confidence: 99%

Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase

Yousif

Stanlie

Mondal

et al. 2014

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

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Activation-induced cytidine deaminase (AID) is essential to classswitch recombination (CSR) and somatic hypermutation (SHM) in both V region SHM and S region SHM (s-SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair (BER) complex, is required for CSR. Strikingly, however, UNG deficiency causes augmentation of SHM, suggesting involvement of distinct functions of UNG in SHM and CSR. Here, we show that noncanonical scaffold functions of UNG regulate s-SHM negatively and CSR positively. The s-SHM suppressive function of UNG is attributed to the recruitment of faithful BER components at the cleaved DNA locus, with competition against error-prone polymerases. By contrast, the CSR-promoting function of UNG enhances AID-dependent S-S synapse formation by recruiting p53-binding protein 1 and DNAdependent protein kinase, catalytic subunit. Several loss-of-catalysis mutants of UNG discriminated CSR-promoting activity from s-SHM suppressive activity. Taken together, the noncanonical function of UNG regulates the steps after AID-induced DNA cleavage: errorprone repair suppression in s-SHM and end-joining promotion in CSR.NHEJ | synapsis

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“…Likewise, AID expressed in bacteria can generate SHM, but again primarily on the nontemplate DNA strand (20). Various findings also suggest that AID may access S regions via a non-R-loop mechanism that may relate to the mechanism by which it accesses variable regions during SHM (3,25). Despite findings that AID targets mainly the nontemplate strand in most in vitro and bacterial experiments, both the template and nontemplate strands are targeted equally by AID during normal SHM and CSR in vivo (11,26,27).…”

mentioning

confidence: 99%

“…Somatic hypermutation (SHM) introduces point mutations at a very high rate in Ig variable region exons, allowing for the generation of antibodies with increased affinity for their antigen (2). Class switch recombination (CSR) promotes replacement of the -constant region (C ) exons with one of a set of downstream constant region exons (C␥3, C␥1, C␥2b, C␥2a, C , and C␣) that encode different effector functions (3). This replacement is achieved by breakage and joining of specialized switch (S) regions that precede every constant region that undergoes CSR.…”

mentioning

confidence: 99%

Antisense transcripts from immunoglobulin heavy-chain locus V(D)J and switch regions

Perlot

Alt

2008

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

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Activation-induced cytosine deaminase (AID) is essential for both somatic hypermutation (SHM) and class switch recombination (CSR), two processes involved in antibody diversification. Previously, various groups showed both in vitro and in vivo that AID initiates SHM and CSR by deaminating cytosines in DNA in a transcription-dependent manner. Although in vivo both DNA strands are equally targeted by AID, many in vitro and bacterial experiments found that AID almost exclusively targets the nontemplate strand of a transcribed substrate. Here, we report the detection of antisense transcripts in assembled Ig heavy chain (IgH) variable region exons and their immediate downstream region, as well as in switch regions, sequences that, respectively, are targets for SHM and CSR in vivo. In contrast, we did not detect antisense transcripts from the C constant region exons, which lie between the IgH variable region exons and downstream S regions and which are not normally an AID target. Expression of the antisense variable region/flanking region and the S-region transcripts were found in all lymphocytes that transcribe these sequences in the sense direction. Steady-state levels of antisense transcripts appeared very low, and start sites potentially appeared heterogeneous. We discuss the potential implications of antisense IgH locus transcription for AID targeting or other processes.class switch recombination ͉ somatic hypermutation ͉ activation-induced cytosine deaminase ͉ bidirectional transcription

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Evolution of the Immunoglobulin Heavy Chain Class Switch Recombination Mechanism

Cited by 233 publications

References 285 publications

Active nuclear import and cytoplasmic retention of activation-induced deaminase

Active nuclear import and cytoplasmic retention of activation-induced deaminase

Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase

Antisense transcripts from immunoglobulin heavy-chain locus V(D)J and switch regions

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