analysis-somatic-hypermutation-jh4-intron-germinal-center-b-cells

Analysis of Somatic Hypermutation in the JH4 intron of Germinal Center B cells from Mouse Peyer's Patches

Within the germinal centers of lymphoid organs, mature B cells alter their expressed immunoglobulin (Ig) by introducing untemplated mutations into the ...

The City College of New York and The Graduate Center of The City University of New York

Adaptive immune responses require the generation of a diverse repertoire of immunoglobulins (Igs) that can recognize and neutralize a seemingly infinite number of antigens. V(D)J recombination creates the primary Ig repertoire, which subsequently is modified by somatic hypermutation (SHM) and class switch recombination (CSR). SHM promotes Ig affinity maturation whereas CSR alters the effector function of the Ig. Both SHM and CSR require activation-induced cytidine deaminase (AID) to produce dU:dG mismatches in the Ig locus that are transformed into untemplated mutations in variable coding segments during SHM or DNA double-strand breaks (DSBs) in switch regions during CSR. Within the Ig locus, DNA repair pathways are diverted from their canonical role in maintaining genomic integrity to permit AID-directed mutation and deletion of gene coding segments. Recently identified proteins, genes, and regulatory networks have provided new insights into the temporally and spatially coordinated molecular interactions that control the formation and repair of DSBs within the Ig locus. Unravelling the genetic program that allows B cells to selectively alter the Ig coding regions while protecting non-Ig genes from DNA damage advances our understanding of the molecular processes that maintain genomic integrity as well as humoral immunity.

Generating and repairing genetically programmed DNA breaks during immunoglobulin class switch recombination.

Activation-induced cytidine deaminase (AID) generates U:G mismatches in Ig genes that can be converted into untemplated mutations during somatic hypermutation or DNA double-strand breaks during class switch recombination (CSR). Null mutations in  and  demonstrate the complementary roles of the base excision repair (BER) and mismatch repair pathways, respectively, in CSR. Phosphorylation of AID at serine 38 was previously hypothesized to regulate BER during CSR, as the AID phosphorylation mutant, AID(S38A), cannot interact with APE1, a BER protein. Consistent with these findings, we observe a complete block in CSR in  mouse B cells that correlates with an impaired mutation frequency at 5'Sμ. Similarly, somatic hypermutation is almost negligible at the JH4 intron in  mouse B cells, and, consistent with this, NP-specific affinity maturation in  mice is not significantly elevated in response to NP-CGG immunization. Surprisingly,  mouse B cells also cannot complete CSR or affinity maturation despite accumulating significant mutations in 5'Sμ as well as the JH4 intron. These data identify a novel role for phosphorylation of AID at serine 38 in mismatch repair-dependent CSR and affinity maturation.

Jee Eun Choi

Department of Biology

The City College of New York and The Graduate Center of The City University of New York

Analysis of Somatic Hypermutation in the JH4 intron of Germinal Center B cells from Mouse Peyer's Patches

Jee Eun Choi

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The City College of New York and The Graduate Center of The City University of New York

Analysis of Somatic Hypermutation in the JH4 intron of Germinal Center B cells from Mouse Peyer's Patches

Department of Biology