Functional analyses of polymorphic variants of human terminal deoxynucleotidyl transferase
| Autor: | Sheng Y, Lina Chen, Saridakis, Wu Ge, Dzneladze I, Troshchynsky A |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Genetics Nucleotides Immunology V(D)J recombination Immunoglobulin Variable Region Receptors Antigen T-Cell Single-nucleotide polymorphism Adaptive Immunity Biology Acquired immune system Polymorphism Single Nucleotide Molecular biology V(D)J Recombination Jurkat Cells Immune system Terminal deoxynucleotidyl transferase Antigen DNA Nucleotidylexotransferase Genetic variation biology.protein Humans Genetics (clinical) Polymerase |
| Zdroj: | Genes & Immunity. 16:388-398 |
| ISSN: | 1476-5470 1466-4879 |
| DOI: | 10.1038/gene.2015.19 |
| Popis: | Human terminal deoxynucleotidyl transferase (hTdT) is a DNA polymerase that functions to generate diversity in the adaptive immune system. Here, we focus on the function of naturally occurring single-nucleotide polymorphisms (SNPs) of hTdT to evaluate their role in genetic-generated immune variation. The data demonstrate that the genetic variations generated by the hTdT SNPs will vary the human immune repertoire and thus its responses. Human TdT catalyzes template-independent addition of nucleotides (N-additions) during coding joint formation in V(D)J recombination. Its activity is crucial to the diversity of the antigen receptors of B and T lymphocytes. We used in vitro polymerase assays and in vivo human cell V(D)J recombination assays to evaluate the activity and the N-addition levels of six natural (SNP) variants of hTdT. In vitro, the variants differed from wild-type hTdT in polymerization ability with four having significantly lower activity. In vivo, the presence of TdT varied both the efficiency of recombination and N-addition, with two variants generating coding joints with significantly fewer N-additions. Although likely heterozygous, individuals possessing these genetic changes may have less diverse B- and T-cell receptors that would particularly effect individuals prone to adaptive immune disorders, including autoimmunity. |
| Databáze: | OpenAIRE |
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