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Transcriptional stalling in B-lymphocytes: a mechanism for antibody diversification and maintenance of genomic integrity.

Sun J, Rothschild G, Pefanis E, Basu U - Transcription (2013)

Bottom Line: B cells utilize three DNA alteration strategies-V(D)J recombination, somatic hypermutation (SHM) and class switch recombination (CSR)-to somatically mutate their genome, thereby expressing a plethora of antibodies tailor-made against the innumerable antigens they encounter while in circulation.Of these three events, the single-strand DNA cytidine deaminase, Activation Induced cytidine Deaminase (AID), is responsible for SHM and CSR.Recent advances, discussed in this review article, point toward various components of RNA polymerase II "stalling" machinery as regulators of AID activity during antibody diversification and maintenance of B cell genome integrity.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology; College of Physicians and Surgeons; Columbia University; New York, NY USA.

ABSTRACT
B cells utilize three DNA alteration strategies-V(D)J recombination, somatic hypermutation (SHM) and class switch recombination (CSR)-to somatically mutate their genome, thereby expressing a plethora of antibodies tailor-made against the innumerable antigens they encounter while in circulation. Of these three events, the single-strand DNA cytidine deaminase, Activation Induced cytidine Deaminase (AID), is responsible for SHM and CSR. Recent advances, discussed in this review article, point toward various components of RNA polymerase II "stalling" machinery as regulators of AID activity during antibody diversification and maintenance of B cell genome integrity.

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Figure 2. Fate of cytidine residues following AID mediated DNA deamination. (A) AID deaminates cytidine residues to uracils that are identified by the cellular base excision repair pathway (UNG) or the mismatch repair pathway (MSH2/MSH6) for repair. Neighboring residues (A/T based pairs) may be mutated in this process of DNA lesion repair that depends upon the DNA polymerase η. (B) Multiple possibilities exist explaining how a lesion could be repaired. Based on the activity of error prone DNA polymerases (DNA pol η), change of the neighboring A/T based pair could be to T/A or G/C or C/G base pairs. The nascently formed uracil residues are substrates of the apurinic endonucleases (APE1/2), and this reaction eventually leads to creation of single-strand DNA (ssDNA) nicks. ssDNA nicks on both strands of switch sequences can generate DNA double strand breaks that are intermediates during CSR.
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Figure 2: Figure 2. Fate of cytidine residues following AID mediated DNA deamination. (A) AID deaminates cytidine residues to uracils that are identified by the cellular base excision repair pathway (UNG) or the mismatch repair pathway (MSH2/MSH6) for repair. Neighboring residues (A/T based pairs) may be mutated in this process of DNA lesion repair that depends upon the DNA polymerase η. (B) Multiple possibilities exist explaining how a lesion could be repaired. Based on the activity of error prone DNA polymerases (DNA pol η), change of the neighboring A/T based pair could be to T/A or G/C or C/G base pairs. The nascently formed uracil residues are substrates of the apurinic endonucleases (APE1/2), and this reaction eventually leads to creation of single-strand DNA (ssDNA) nicks. ssDNA nicks on both strands of switch sequences can generate DNA double strand breaks that are intermediates during CSR.

Mentions: Following antigen exposure in the germinal center, B cells proliferate and undergo CSR and SHM.2 Transcriptional activation of various regions of the IgH locus leads to epigenetic and structural changes of genes in the coding and non-coding regions of the variable and constant regions. Such changes are required for the B cell mutator Activation Induced cytidine Deaminase (AID) to access these substrate DNA sequences.6,7 Various lines of evidence, previously summarized,7 have established that AID mutates single-stranded (ss) DNA in vitro and potentially in vivo as well. These studies have demonstrated that AID deaminates deoxycytidine residues (dC) to deoxyuridines (dU) which are then either repaired as deoxycytidines, replicated through during DNA replication to introduce a deoxythymidine (dT) in one daughter cell, or converted to dA, dG or dT by the coordinated actions of the cellular base excision repair and mis-match repair machinery. A schematic representation of the mutagenesis of an AID target dC residue is shown in Figure 2, where it is also explain how neighboring residues of AID-deaminated dCs can be subjected to mutagenesis due to the action of the error-prone DNA polymerase, polη8. Other published reviews can provide a better and more detailed overview of the mechanisms that govern the specifications and behavior of AID-induced mutagenesis shown in Figure 2.9-11


Transcriptional stalling in B-lymphocytes: a mechanism for antibody diversification and maintenance of genomic integrity.

Sun J, Rothschild G, Pefanis E, Basu U - Transcription (2013)

Figure 2. Fate of cytidine residues following AID mediated DNA deamination. (A) AID deaminates cytidine residues to uracils that are identified by the cellular base excision repair pathway (UNG) or the mismatch repair pathway (MSH2/MSH6) for repair. Neighboring residues (A/T based pairs) may be mutated in this process of DNA lesion repair that depends upon the DNA polymerase η. (B) Multiple possibilities exist explaining how a lesion could be repaired. Based on the activity of error prone DNA polymerases (DNA pol η), change of the neighboring A/T based pair could be to T/A or G/C or C/G base pairs. The nascently formed uracil residues are substrates of the apurinic endonucleases (APE1/2), and this reaction eventually leads to creation of single-strand DNA (ssDNA) nicks. ssDNA nicks on both strands of switch sequences can generate DNA double strand breaks that are intermediates during CSR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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Figure 2: Figure 2. Fate of cytidine residues following AID mediated DNA deamination. (A) AID deaminates cytidine residues to uracils that are identified by the cellular base excision repair pathway (UNG) or the mismatch repair pathway (MSH2/MSH6) for repair. Neighboring residues (A/T based pairs) may be mutated in this process of DNA lesion repair that depends upon the DNA polymerase η. (B) Multiple possibilities exist explaining how a lesion could be repaired. Based on the activity of error prone DNA polymerases (DNA pol η), change of the neighboring A/T based pair could be to T/A or G/C or C/G base pairs. The nascently formed uracil residues are substrates of the apurinic endonucleases (APE1/2), and this reaction eventually leads to creation of single-strand DNA (ssDNA) nicks. ssDNA nicks on both strands of switch sequences can generate DNA double strand breaks that are intermediates during CSR.
Mentions: Following antigen exposure in the germinal center, B cells proliferate and undergo CSR and SHM.2 Transcriptional activation of various regions of the IgH locus leads to epigenetic and structural changes of genes in the coding and non-coding regions of the variable and constant regions. Such changes are required for the B cell mutator Activation Induced cytidine Deaminase (AID) to access these substrate DNA sequences.6,7 Various lines of evidence, previously summarized,7 have established that AID mutates single-stranded (ss) DNA in vitro and potentially in vivo as well. These studies have demonstrated that AID deaminates deoxycytidine residues (dC) to deoxyuridines (dU) which are then either repaired as deoxycytidines, replicated through during DNA replication to introduce a deoxythymidine (dT) in one daughter cell, or converted to dA, dG or dT by the coordinated actions of the cellular base excision repair and mis-match repair machinery. A schematic representation of the mutagenesis of an AID target dC residue is shown in Figure 2, where it is also explain how neighboring residues of AID-deaminated dCs can be subjected to mutagenesis due to the action of the error-prone DNA polymerase, polη8. Other published reviews can provide a better and more detailed overview of the mechanisms that govern the specifications and behavior of AID-induced mutagenesis shown in Figure 2.9-11

Bottom Line: B cells utilize three DNA alteration strategies-V(D)J recombination, somatic hypermutation (SHM) and class switch recombination (CSR)-to somatically mutate their genome, thereby expressing a plethora of antibodies tailor-made against the innumerable antigens they encounter while in circulation.Of these three events, the single-strand DNA cytidine deaminase, Activation Induced cytidine Deaminase (AID), is responsible for SHM and CSR.Recent advances, discussed in this review article, point toward various components of RNA polymerase II "stalling" machinery as regulators of AID activity during antibody diversification and maintenance of B cell genome integrity.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology; College of Physicians and Surgeons; Columbia University; New York, NY USA.

ABSTRACT
B cells utilize three DNA alteration strategies-V(D)J recombination, somatic hypermutation (SHM) and class switch recombination (CSR)-to somatically mutate their genome, thereby expressing a plethora of antibodies tailor-made against the innumerable antigens they encounter while in circulation. Of these three events, the single-strand DNA cytidine deaminase, Activation Induced cytidine Deaminase (AID), is responsible for SHM and CSR. Recent advances, discussed in this review article, point toward various components of RNA polymerase II "stalling" machinery as regulators of AID activity during antibody diversification and maintenance of B cell genome integrity.

Show MeSH