Article ; Online: XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination.
2016 Volume 128, Issue 5, Page(s) 650–659
Abstract: ... during V(D)J (variable [V], diversity [D], and joining [J] genes) recombination of their antigen receptor ... 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 ...
| Abstract | 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. |
|---|---|
| MeSH term(s) | Animals ; Antigens/metabolism ; Complementarity Determining Regions/genetics ; DNA Nucleotidylexotransferase/metabolism ; DNA Repair Enzymes/deficiency ; DNA Repair Enzymes/metabolism ; DNA-Binding Proteins/deficiency ; DNA-Binding Proteins/metabolism ; Gene Rearrangement/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Immunoglobulins/genetics ; Mice ; Nucleotides/metabolism ; Radiation, Ionizing ; Receptors, Antigen, T-Cell/genetics ; V(D)J Recombination/genetics |
| Chemical Substances | Antigens ; Complementarity Determining Regions ; DNA-Binding Proteins ; Immunoglobulins ; NHEJ1 protein, human ; Nucleotides ; Receptors, Antigen, T-Cell ; XLF protein, mouse ; DNA Nucleotidylexotransferase (EC 2.7.7.31) ; DNA Repair Enzymes (EC 6.5.1.-) |
| Language | English |
| Publishing date | 2016-06-08 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 80069-7 |
| ISSN | 1528-0020 ; 0006-4971 |
| ISSN (online) | 1528-0020 |
| ISSN | 0006-4971 |
| DOI | 10.1182/blood-2016-02-701029 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Uh III Zs.140: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
|||
| Zs.MO 364: Show issues |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.