A coming-of-age story: activation-induced cytidine deaminase turns 10

Delker, Rebecca K; Fugmann, Sebastian D.; Papavasiliou, F. Nina

doi:10.1038/ni.1799

Cited by 92 publications

(79 citation statements)

References 107 publications

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“…Multiple mechanisms may operate to regulate the specificity and efficiency of AID targeting (48,49). Whether and how the target DNA sequences influence mutation frequency has not been clearly addressed.…”

Section: Discussionmentioning

confidence: 99%

“…The effects of cis-acting elements of Ig loci in SHM have been investigated extensively (2,(55)(56)(57)(58). However, none of the known transcriptional control elements in mouse B cells appears to be absolutely required for SHM, suggesting a redundancy or unidentified elements (48). Recent studies discovered novel cis-acting elements in the IgL locus of the DT40 chicken B cell line that are both essential and sufficient for AIDmediated sequence diversification (59,60).…”

Section: Discussionmentioning

confidence: 99%

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Target DNA Sequence Directly Regulates the Frequency of Activation-Induced Deaminase-Dependent Mutations

Chen

Viboolsittiseri

O’Connor

et al. 2012

The Journal of Immunology

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Activation-induced deaminase (AID) catalyses class switch recombination (CSR) and somatic hypermutation (SHM) in B lymphocytes to enhance Ab diversity. CSR involves breaking and rejoining highly repetitive switch (S) regions in the IgH (Igh) locus. S regions appear to be preferential targets of AID. To determine whether S region sequence per se, independent of Igh cis regulatory elements, can influence AID targeting efficiency and mutation frequency, we established a knock-in mouse model by inserting a core Sγ1 region into the first intron of proto-oncogene Bcl6, which is a non-Ig target of SHM. We found that the mutation frequency of the inserted Sγ1 region was dramatically higher than that of the adjacent Bcl6 endogenous sequence. Mechanistically, S region-enhanced SHM was associated with increased recruitment of AID and RNA polymerase II, together with Spt5, albeit to a lesser extent. Our studies demonstrate that target DNA sequences influence mutation frequency via regulating AID recruitment. We propose that the nucleotide sequence preference may serve as an additional layer of AID regulation by restricting its mutagenic activity to specific sequences despite the observation that AID has the potential to access the genome widely.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Target DNA Sequence Directly Regulates the Frequency of Activation-Induced Deaminase-Dependent Mutations

Chen

Viboolsittiseri

O’Connor

et al. 2012

The Journal of Immunology

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“…This approach makes possible both de novo discovery and maturation from a naïve antibody library and may also be used for maturation of preexisting antibodies. In vitro affinity maturation by SHM has been described in human B cell lymphoma lines (32), chicken DT40 cells (33,34), CHO cells (4), and 18-81 cells (35). However, these cell lines are difficult to transfect at efficiencies suitable for use with diverse libraries.…”

Section: Discussionmentioning

confidence: 99%

Coupling mammalian cell surface display with somatic hypermutation for the discovery and maturation of human antibodies

Bowers

Horlick

Neben

et al. 2011

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

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A novel approach has been developed for the isolation and maturation of human antibodies that replicates key features of the adaptive immune system by coupling in vitro somatic hypermutation (SHM) with mammalian cell display. SHM is dependent on the action of the B cell specific enzyme, activation-induced cytidine deaminase (AID), and can be replicated in non-B cells through expression of recombinant AID. A library of human antibodies, based on germline V-gene segments with recombined human D J regions was used to isolate low-affinity antibodies to human β nerve growth factor (hβNGF). These antibodies, initially naïve to SHM, were subjected to AID-directed SHM in vitro and selected using the same mammalian cell display system, as illustrated by the maturation of one of the antibodies to low pM K D . This approach overcomes many of the previous limitations of mammalian cell display, enabling direct selection and maturation of antibodies as full-length, glycosylated IgGs. affinity maturation | mammalian display

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“…Since the discovery of AID and its role in SHM and CSR, [43][44][45] an immense amount of effort has been directed toward deciphering how the enzyme functions and determining how it is regulated. 46 Regulation has been proposed at many different levels, including transcription, 47 mRNA degradation by miRNAs, 48 cellular localization and active nuclear shuttling, 49 post-translational modifications, 50,51 proteasomal degradation 52 and by interaction with various cellular partners. [53][54][55] It is intriguing to note that AID expression is augmented in B cell-derived lymphomas and leukemias, 56 and there is increasing evidence that AID upregulation by proinflammatory cytokines in tissues other than B cells can promote tumorigenesis.…”

Section: Regulation Of Apobec3 Activitymentioning

confidence: 99%