AID mutates a non-immunoglobulin transgene independent of chromosomal position

Parsa, Jahan-Yar; Basit, Wajiha; Wang, Clifford L.; Gommerman, Jennifer L.; Carlyle, James R.; Martín, Alberto

doi:10.1016/j.molimm.2006.02.003

Cited by 31 publications

(19 citation statements)

References 64 publications

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Section: Aid Levels Correlate With Apoptosis and Dsdna-break Formatiomentioning

confidence: 71%

“…This is probably the result of the fact that the mutation rates in both clones are similar, 8 which suggests the presence of a factor that is required for AID activity but is present in a limiting amount, as previously discussed. 32 These results indicate that the observed changes in apoptotic levels in Ramos cells are an AID-dependent effect.Because of the ability of AID to generate dsDNA breaks, we hypothesized that these events may be responsible for inducing cell-stress pathways. We previously showed that exogenous plasmid DNA incorporates into sites of dsDNA breaks caused by AID in hybridomas.…”

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confidence: 71%

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AID constrains germinal center size by rendering B cells susceptible to apoptosis

Zaheen

Boulianne

Parsa

et al. 2009

Blood

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IntroductionA fundamental hallmark of humoral immunity is the ability to produce class-switched antibodies that have enhanced affinity for antigen. This process, termed affinity maturation, allows clonally selected B cells to refine their response to theoretically target any antigen with high specificity. After activation, B cells mutate the immunoglobulin (Ig) locus in a process known as somatic hypermutation (SHM). 1 Mutated clones that have acquired increased affinity for antigen preferentially expand over their low-affinity counterparts. The selection process occurs in the germinal center (GC), a transient microenvironment that forms in secondary lymphoid tissue shortly after antigen exposure. 2 The GC provides a competitive setting for B cells whereby ineffectual clones are actively cleared from the system via apoptosis, although the processes that govern this selection still remain vague.SHM and class switch recombination (CSR) are initiated by the enzyme activation-induced cytidine deaminase (AID), 3,4 which deaminates cytidines to uridines specifically at the Ig locus. 5-10 AID-generated uridines are then engaged by various DNA repair pathways that either lead to the generation of point mutations in the antibody variable region or recombinogenic events that lead to CSR. AID Ϫ/Ϫ mice lack mutations at their Ig locus and are incapable of producing class-switched antibodies. 4 Interestingly, these mice were previously shown to harbor an abnormally high proportion of splenic GC B cells. 11 This phenotype is also recapitulated in humans with AID deficiencies. 3 Although a link between reduced gut immunity (resulting from an inability to produce mucosal IgA) and peripheral GC formation was hypothesized to account for these abnormalities, this remains to be conclusively proven, and the possibility of a B cell-intrinsic effect that could explain the profound expansion of GC B cells has not been examined.GC B cells represent a unique lymphoid compartment of actively proliferating cells where numerous apoptotic factors must synergize to induce the elimination of nonproductive clones. Factors contributing to the intrinsic pathway of apoptosis, such as Bcl-2, Bcl-x L , and Bim, 12-17 and the extrinsic pathway, such as Fas, [18][19][20][21][22] have been implicated in GC selection. The unique physiology of these cells makes them highly susceptible to disease progression, often serving as etiologic sites for autoimmune and malignant B cells. 13,[23][24][25][26] Recent evidence has implicated AID as a fundamental contributor to the genetic aberrations that lead to these disease phenotypes. 24,[27][28][29] Given the importance of apoptosis as a parameter for both GC B-cell selection and lymphomagenesis, we investigated the relationship between AID-induced DNA mutation and cell death to understand how this enzyme may impinge on survival and death within the GC niche. Here we report that many of the potentially harmful AID-induced genetic alterations may indeed lead to the death of these cells within the GC. Methods Mice...

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Section: Aid Levels Correlate With Apoptosis and Dsdna-break Formatiomentioning

confidence: 71%

mentioning

confidence: 71%

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Zaheen

Boulianne

Parsa

et al. 2009

Blood

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“…Thus, the biological significance of AID binding to many of its putative co-factors is a topic that requires further resolution. Furthermore, the very premise of searching for cofactors to explain regulation of AID targeting may be flawed in that the more AID is studied, the clearer it becomes that its activity is rather not tightly regulated: despite a modest preference for Ig loci which appears to be mediated by unique transcriptional features (101–103), AID mutates endogenous genes and transgenes genome-wide, and can do so in any cell type in which it is naturally or exogenously expressed (10, 104–107). …”

Section: Catalytic Pocket Occlusion As Internally Built-in Regulationmentioning

confidence: 99%

A Novel Regulator of Activation-Induced Cytidine Deaminase/APOBECs in Immunity and Cancer: Schrödinger’s CATalytic Pocket

King

Larijani

2017

Front. Immunol.

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Activation-induced cytidine deaminase (AID) and its relative APOBEC3 cytidine deaminases boost immune response by mutating immune or viral genes. Because of their genome-mutating activities, AID/APOBECs are also drivers of tumorigenesis. Due to highly charged surfaces, extensive non-specific protein–protein/nucleic acid interactions, formation of polydisperse oligomers, and general insolubility, structure elucidation of these proteins by X-ray crystallography and NMR has been challenging. Hence, almost all available AID/APOBEC structures are of mutated and/or truncated versions. In 2015, we reported a functional structure for AID using a combined computational–biochemical approach. In so doing, we described a new regulatory mechanism that is a first for human DNA/RNA-editing enzymes. This mechanism involves dynamic closure of the catalytic pocket. Subsequent X-ray and NMR studies confirmed our discovery by showing that other APOBEC3s also close their catalytic pockets. Here, we highlight catalytic pocket closure as an emerging and important regulatory mechanism of AID/APOBEC3s. We focus on three sub-topics: first, we propose that variable pocket closure rates across AID/APOBEC3s underlie differential activity in immunity and cancer and review supporting evidence. Second, we discuss dynamic pocket closure as an ever-present internal regulator, in contrast to other proposed regulatory mechanisms that involve extrinsic binding partners. Third, we compare the merits of classical approaches of X-ray and NMR, with that of emerging computational–biochemical approaches, for structural elucidation specifically for AID/APOBEC3s.

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“…Indeed, the significant increase in mutation frequency from follicular B cells to GC B cells could be because of AID's promiscuous activity. 22,[32][33][34][35][36][37] To determine whether the lacI transgene could be a target of AID, we first tested whether the lacI gene is transcribed in B cells. We carried out a reversetranscriptase PCR by using random hexamers (in case the lacI transcript is not polyadenylated) on RNA isolated from splenocytes from BB Ϫ and BB ϩ WT mice.…”

Section: Aid Does Not Mutate the Laci Transgenementioning

confidence: 99%

The mismatch repair pathway functions normally at a non-AID target in germinal center B cells

Green

Belcheva

Nepal

et al. 2011

Blood

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IntroductionMismatch repair (MMR) is an evolutionary conserved DNA repair pathway that is required to repair mutations that arise through DNA replication or other processes. 1,2 MutS homologue 2 (Msh2) dimerizes with either Msh6 or Msh3 to recognize single base-pair mismatches or mismatches caused by insertion/deletions, respectively. 2 After binding to the mismatch, Msh2 hydrolyzes ATP, which induces a change in the heterodimer that allows for the recruitment of downstream repair factors such as MutL homologue 1, postmeiotic segregation 2, and exonuclease 1 (Exo1). 3,4 Because of Msh2's essential role in repairing DNA mutations, Msh2 Ϫ/Ϫ mice have 5-fold, 11-fold, and 15-fold greater mutation frequencies in the brain, small intestine, and thymus, respectively, 5 and are predisposed to cancer. [6][7][8] During an immune response, Ig genes undergo somatic hypermutation (SHM) to produce high-affinity antibodies. SHM is initiated by activation-induced cytidine deaminase (AID), 9 which deaminates cytidine molecules within the V region to produce dU:dG mispairs. [10][11][12] The dU:dG mismatch is recognized by the Msh2/Msh6 heterodimer, but instead of repairing this mutation, MMR produces mutations. [13][14][15][16][17][18] Mice deficient in Msh2, Msh6, postmeiotic segregation 2, MutL homologue 1, or Exo1 have an approximately 2-fold decrease in overall mutation frequency at the V region. 13,14,[16][17][18] In particular, there is an approximately10-fold decrease in mutations at A:T base pairs at the V region in MSH2-deficient mice, whereas the mutation frequency at G:C base pairs is unaltered. [15][16][17][18][19] These results indicate that the MMR pathway is required to produce mutations at A:T base pairs in the V region. MMR proteins have also been implicated in mutagenic processes that cause disease, including trinucleotide-repeat diseases. 20 Two sets of recent results suggest the possibility that the MMR system is generally defective in germinal center (GC) B cells.Ouchida et al 21 reported that GC B cells have a generally greater mutation rate than other cells, as measured by the frequency of mutations on a lacZ transgene. Liu et al 22 found that in Msh2 mutant mice, the mutation frequency of AID-sensitive genes was either lower or only slightly greater than in wild-type (WT) cells; they argued that the Msh2-dependent pathway was not functioning normally in GC cells. Together, these results would fit a simple unified model in which the expression of a GC/B cell-specific factor commandeers MMR and transforms this DNA repair pathway into a mutagenic pathway.An alternative explanation is that the MMR pathway is only mutagenic at sites mutated by AID, which would argue against a factor that disrupts global MMR function in GC B cells. To explore this issue, we examined the impact of Msh2-deficiency at a lacI transgene that is not mutated by AID in GC B cells. Our results indicate that Msh2 efficiently repairs lacI mutations in all cell populations examined, including GC B cells. Thus, MMR functions normally in GC ...

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AID mutates a non-immunoglobulin transgene independent of chromosomal position

Cited by 31 publications

References 64 publications

AID constrains germinal center size by rendering B cells susceptible to apoptosis

AID constrains germinal center size by rendering B cells susceptible to apoptosis

A Novel Regulator of Activation-Induced Cytidine Deaminase/APOBECs in Immunity and Cancer: Schrödinger’s CATalytic Pocket

The mismatch repair pathway functions normally at a non-AID target in germinal center B cells

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