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Rad52 competes with Ku70/Ku86 for binding to S-region DSB ends to modulate antibody class-switch DNA recombination.
- Source :
-
Nature communications [Nat Commun] 2017 Feb 08; Vol. 8, pp. 14244. Date of Electronic Publication: 2017 Feb 08. - Publication Year :
- 2017
-
Abstract
- Antibody class-switch DNA recombination (CSR) is initiated by AID-introduced DSBs in the switch (S) regions targeted for recombination, as effected by Ku70/Ku86-mediated NHEJ. Ku-deficient B cells, however, undergo (reduced) CSR through an alternative(A)-NHEJ pathway, which introduces microhomologies in S-S junctions. As microhomology-mediated end-joining requires annealing of single-strand DNA ends, we addressed the contribution of single-strand annealing factors HR Rad52 and translesion DNA polymerase θ to CSR. Compared with their Rad52 <superscript>+/+</superscript> counterparts, which display normal CSR, Rad52 <superscript>-/-</superscript> B cells show increased CSR, fewer intra-Sμ region recombinations, no/minimal microhomologies in S-S junctions, decreased c-Myc/IgH translocations and increased Ku70/Ku86 recruitment to S-region DSB ends. Rad52 competes with Ku70/Ku86 for binding to S-region DSB ends. It also facilitates a Ku-independent DSB repair, which favours intra-S region recombination and mediates, particularly in Ku absence, inter-S-S recombination, as emphasized by the significantly greater CSR reduction in Rad52 <superscript>-/-</superscript> versus Rad52 <superscript>+/+</superscript> B cells on Ku86 knockdown.
- Subjects :
- Animals
B-Lymphocytes immunology
B-Lymphocytes metabolism
Cytidine Deaminase genetics
Cytidine Deaminase immunology
Cytidine Deaminase metabolism
DNA Breaks, Double-Stranded
DNA End-Joining Repair genetics
DNA-Directed DNA Polymerase genetics
DNA-Directed DNA Polymerase immunology
DNA-Directed DNA Polymerase metabolism
Female
Gene Knockdown Techniques
Humans
Immunoglobulin Class Switching immunology
Immunoglobulin Switch Region genetics
Ku Autoantigen genetics
Ku Autoantigen immunology
Ku Autoantigen metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
RNA, Small Interfering metabolism
Rad52 DNA Repair and Recombination Protein genetics
Rad52 DNA Repair and Recombination Protein immunology
Sulfonamides
DNA Polymerase theta
DNA End-Joining Repair immunology
Immunoglobulin Class Switching genetics
Rad52 DNA Repair and Recombination Protein metabolism
Recombinational DNA Repair immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 8
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 28176781
- Full Text :
- https://doi.org/10.1038/ncomms14244