DNA polymerases in adaptive immunity

• Published in: Nature reviews. Immunology Vol. 8; no. 4; pp. 302 - 312
• Main Authors: Weill, Jean-Claude, Reynaud, Claude-Agnès
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2008; Nature Publishing Group
• Subjects: Animals; Antigens; B-Lymphocytes; B-Lymphocytes - enzymology; Biomedical and Life Sciences; Biomedicine; Deoxyribonucleic acid; DNA; DNA polymerase; DNA polymerases; DNA repair; DNA-Directed DNA Polymerase; DNA-Directed DNA Polymerase - metabolism; Enzymes; Gene Conversion; Gene Conversion - physiology; Genes; Health aspects; Humans; Immune response; Immune system; Immunity, Active; Immunity, Active - physiology; Immunoglobulin Class Switching; Immunoglobulin Class Switching - physiology; Immunoglobulins; Immunology; Life Sciences; Mutagenesis; Mutation; Physiological aspects; review-article; Somatic Hypermutation, Immunoglobulin; Somatic Hypermutation, Immunoglobulin - physiology; France; diversity; repertoire; polymerase; immunoglobulin genes
• ISSN: 1474-1733; 1474-1741; 1474-1741
• DOI: 10.1038/nri2281

Key Points Multiple molecular events take place during the life of a B cell, first when the B-cell receptor (BCR) is assembled in the bone marrow during the generation of the pre-immune repertoire and later during an immune response in secondary lymphoid organs through the process of affinity maturation (known as somatic hypermutation, SHM) and isotype switching. Specific DNA polymerases are involved at each of these molecular steps. Mammals have 15 DNA polymerases (including terminal deoxynucleotidyl transferase). Four are involved in semi-conservative replication and 11 are involved in different tasks, such as the removal of damaged bases (Polβ), the rejoining of DNA ends during non-homologous end joining (NHEJ) (Polλ and Polμ) and the bypass of DNA lesions that block the replication fork (Y family polymerases and Polζ). The assembly of the immunoglobulin receptor involves the joining of immunoglobulin coding regions that are distantly located in the genome. These coding ends are subject to several enzymatic activities that include nucleotide trimming and template-dependent and -independent DNA synthesis. A large diversity is thus created at the sites of the exon junctions, by varying the length of the complementarity-determining region 3 (CDR3). Polλ and Polμ participate in these processes, being involved during the recombination of the heavy- and light-chain loci, respectively. During SHM, mostly point mutations are introduced in the variable heavy- and light-chain genes of the BCR presented by B cells engaged in an immune response. The mechanism is initiated by the deamination of cytidines into uracils through the action of activation-induced cytidine deaminase (AID). Thereafter, these U-G mismatches are recognized by two different repair pathways, mediated by either uracil glycosylase (UNG) or the mismatch recognition complex, MSH2–MSH6. Two DNA polymerases have been shown unequivocally to be recruited during these error-prone repair processes: Polη, which generates all mutations at A/T bases during the normal physiological SHM process, and Rev1, which contributes some of the G/C mutation transversion mutations. A model for SHM is proposed that attempts to include all the data collected from various mouse and human experimental settings. In this model, the two repair pathways involved in SHM appear to function outside of their normal roles in the base-excision repair or mismatch repair processes, and to compete rather than collaborate once the U-G mismatches have been generated by AID. The development of a diverse B-cell repertoire depends on genetic rearrangement and hypermutation at the B-cell receptor (BCR) loci. This Review describes which DNA polymerases might be involved in these DNA transactions and therefore contribute to BCR diversity. To cope with an unpredictable variety of potential pathogenic insults, the immune system must generate an enormous diversity of recognition structures, and it does so by making stepwise modifications at key genetic loci in each lymphoid cell. These modifications proceed through the action of lymphoid-specific proteins acting together with the general DNA-repair machinery of the cell. Strikingly, these general mechanisms are usually diverted from their normal functions, being used in rather atypical ways in order to privilege diversity over accuracy. In this Review, we focus on the contribution of a set of DNA polymerases discovered in the past decade to these unique DNA transactions.