XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination
| Autor: | Andrew P. Stubbs, Mirjam van der Burg, Dik C. van Gent, Turkan Patiroglu, Jacob Rozmus, Robert A. Holt, Jacques J.M. van Dongen, Klaus Schwarz, Ingrid Pico-Knijnenburg, Erik J. Simons, H. Haluk Akar, Ricardo Leite, Myriam Ricarda Lorenz, David van Zessen, René L. Warren, Isabel S. Jerchel, Hanna IJspeert, Nicole S. Verkaik, Angela Wawer |
|---|---|
| Přispěvatelé: | Immunology, Pathology, Molecular Genetics |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Immunology Receptors Antigen T-Cell Immunoglobulins LIG4 Biology Biochemistry Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine DNA Nucleotidylexotransferase Radiation Ionizing Animals Humans Antigens Immunobiology Gene Rearrangement Nucleotides V(D)J recombination High-Throughput Nucleotide Sequencing Cell Biology Hematology DNA repair protein XRCC4 Complementarity Determining Regions Molecular biology V(D)J Recombination Junctional diversity DNA-Binding Proteins Non-homologous end joining DNA Repair Enzymes 030104 developmental biology Terminal deoxynucleotidyl transferase chemistry 030220 oncology & carcinogenesis Recombination DNA |
| Zdroj: | Blood, 128(5), 650-659. American Society of Hematology |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Repair of DNA double-strand breaks (DSBs) by the nonhomologous end-joining pathway (NHEJ) is important not only for repair of spontaneous breaks but also for breaks induced in developing lymphocytes during V(D)J (variable [V], diversity [D], and joining [J] genes) recombination of their antigen receptor loci to create a diverse repertoire. Mutations in the NHEJ factor XLF result in extreme sensitivity for ionizing radiation, microcephaly, and growth retardation comparable to mutations in LIG4 and XRCC4, which together form the NHEJ ligation complex. However, the effect on the immune system is variable (mild to severe immunodeficiency) and less prominent than that seen in deficiencies of NHEJ factors ARTEMIS and DNA-dependent protein kinase catalytic subunit, with defects in the hairpin opening step, which is crucial and unique for V(D)J recombination. Therefore, we aimed to study the role of XLF during V(D)J recombination. We obtained clinical data from 9 XLF-deficient patients and performed immune phenotyping and antigen receptor repertoire analysis of immunoglobulin (Ig) and T-cell receptor (TR) rearrangements, using next-generation sequencing in 6 patients. The results were compared with XRCC4 and LIG4 deficiency. Both Ig and TR rearrangements showed a significant decrease in the number of nontemplated (N) nucleotides inserted by terminal deoxynucleotidyl transferase, which resulted in a decrease of 2 to 3 amino acids in the CDR3. Such a reduction in the number of N-nucleotides has a great effect on the junctional diversity, and thereby on the total diversity of the Ig and TR repertoire. This shows that XLF has an important role during V(D)J recombination in creating diversity of the repertoire by stimulating N-nucleotide insertion. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|