UNG protects B cells from AID-induced telomere loss

Elena M Cortizas, Astrid Zahn, Shiva Safavi, Joseph A Reed, Francisco Vega, Javier M Di Noia, Ramiro E Verdun, Elena M Cortizas, Astrid Zahn, Shiva Safavi, Joseph A Reed, Francisco Vega, Javier M Di Noia, Ramiro E Verdun

Abstract

Activation-induced deaminase (AID) initiates antibody gene diversification by creating G:U mismatches in the immunoglobulin loci. However, AID also deaminates nonimmunoglobulin genes, and failure to faithfully repair these off-target lesions can cause B cell lymphoma. In this study, we identify a mechanism by which processing of G:U produced by AID at the telomeres can eliminate B cells at risk of genomic instability. We show that telomeres are off-target substrates of AID and that B cell proliferation depends on protective repair by uracil-DNA glycosylase (UNG). In contrast, in the absence of UNG activity, deleterious processing by mismatch repair leads to telomere loss and defective cell proliferation. Indeed, we show that UNG deficiency reduces B cell clonal expansion in the germinal center in mice and blocks the proliferation of tumor B cells expressing AID. We propose that AID-induced damage at telomeres acts as a fail-safe mechanism to limit the tumor promoting activity of AID when it overwhelms uracil excision repair.

© 2016 Cortizas et al.

Figures

Figure 1.
Figure 1.
AID interacts with telomeres in B cells during CSR. (A) Schematic depiction of similarities between telomeres and S regions and location of AID’s preferred target sequences (WRCY). Note that WRCY motifs are present in both S-region strands but exclusively in the C-rich strand in telomeres. Sub-tel, subtelomeric. RPA, replication protein A; V, variable region. (B) Western blot analysis of AID expression in CH12F3 cells after cytokine stimulation for CSR. (C) Representative dot blot analysis of ChIP assays using anti-AID and IgG control in stimulated CH12F3 B cells. Dot blots with 5% of the input or the immunoprecipitates were analyzed via Southern blot with telomeric or Alu repeat probes. (D) Quantification of AID accumulation at telomeres (Telo) and Alu repeats by dot blot, as in C, as well as Sμ and Cμ regions of the Igh locus (by quantitative PCR [Q-PCR]) in CH12F3 cells stimulated for CSR, from at least three independent experiments. post-stim., post-stimulation. Error bars represent SD. (E, left) Western blot analysis of AID expression in CH12F3 cells expressing the indicated shRNAs. (Right) Representative ChIPs in CH12F3 B cells with the indicated antibodies out of three independent experiments. Coimmunoprecipitated telomeric DNA was detected via Southern blot with a telomeric (tel.) probe in dot blots. (F) One representative of three independent ChIP assays, as in C but in splenic B cells purified from Aicda+/+ or Aicda−/− mice, and stimulated with LPS and IL-4 for 72 h. ChIP for the telomeric (Tel) protein TRF1 was included as a positive control. (G) ChIPs in CH12F3 B cells with the indicated antibodies. (Right) Quantification of the dot blot signals after hybridization with a telomeric probe. (H) Northern blot with a telomeric probe showing the level of telomeric transcripts in wild-type splenic B cells before and after stimulation for CSR. EtBr, ethidium bromide. (Right) Quantification of Northern signals. (G and H) Data show mean + SD values obtained at each time point from three independent experiments.
Figure 2.
Figure 2.
AID induces telomere loss in UNG-deficient B cells. (A) Possible outcomes after AID-dependent DNA deaminations are processed by UNG in B cells. (B, left) Illustration of typical FISH staining with a telomere-specific probe in metaphase chromosomes from normal cells and cells with STL. (Right) Effect of UNG inhibition via Ugi expression on the proportion of metaphases with STL in different CH12F3 lines expressing scrambled (scr) control or two different shRNAs that deplete AID, before and after stimulating for CSR to IgA. Post-stim., post-simulation. (C, left) Representative pictures of FISH on metaphase chromosomes in wild-type, Ung−/−, and Ung−/− Aicda−/− mouse splenic B cells stimulated for CSR to IgG1. Telomeres were hybridized with an Alexa Fluor 488–[TTAGGG]4 probe (in green); total DNA was stained with DAPI (in blue). Arrowheads indicate missing telomere staining from single sister chromatids. Bars, 2 µm. (Right) Quantification of STL per metaphase after FISH analysis. Error bars represent mean + SD from at least three independent experiments. (D, left) Western analysis of wild-type AID or AIDE58A levels in CH12F3 Ugi cells. (Right) Quantification of metaphases with STL from CH12F3 Ugi cells expressing GFP, AID, or AIDE58A. (E, left) Illustration of CO-FISH staining. Leading-strand telomeres are shown in red, and lagging-strand telomeres are in green. (Middle) Representative pictures of CO-FISH in B cells at 4 d after stimulation with LPS and IL-4. Arrowheads indicate missing telomere staining from leading-strand telomeres. Bars, 2 µm. (Right) Quantification of STL per metaphase after CO-FISH analysis. (B, D, and E) Data show the mean + SD of three independent experiments, in which 50 metaphases per cell line were analyzed in each experiment.
Figure 3.
Figure 3.
Mismatch repair factors mediate AID-induced STL in Ung-deficient B cells. (A) Possible outcomes of MSH2/MSH6-initiated repair of AID-induced DNA deaminations in B cells. (B) Western blot analysis of MSH2 in CH12F3 cells expressing the indicated shRNAs. scr, scrambled. (C) Quantification of the proportion of STL per 50 metaphases in each of the different CH12F3 lines expressing or not expressing Ugi and scrambled control or two different shRNAs that deplete MSH2, before and after stimulation of CSR to IgA. Error bars represent mean + SD from at least three independent experiments. (D, left) Representative ChIP performed with the indicated antibodies in wild-type, Ung−/−, and Ung−/− Aicda−/− splenic B cells stimulated for CSR to IgG1 and analyzed by dot blotting using telomeric or Alu probes. (Right) Plot of the mean + SD dot blot signals for the telomeric probe from three independent experiments. (E) UNG activity assay using a fluorescein-labeled oligonucleotide containing a single dU, incubated with cell extracts (10 µg protein) from the indicated CH12F3 lines used in C. Substrate and product, indicated on the left, were resolved on 15% TBE-urea polyacrylamide gels. Western blot of γ-tubulin level was used as a loading control. (F) Terminal restriction fragment analysis of TTAGGG repeats in stimulated CH12F3 and CH12F3-Ugi cells expressing the indicated shRNAs via Southern blotting in native or denatured conditions. sub-tel., subtelomeric. (G, left) Diagram showing the expected outcomes after treatment of genomic DNA with exonuclease I before the TRF analyses of TTAGGG repeats. The 3′ to 5′ single-strand exonuclease activity of ExoI will remove the telomeric 3′ G-rich overhang. Therefore, the signal for single-stranded TTAGGG repeats will be lost in a TRF analysis in native conditions. However, in telomeres with short gaps or nicks in the C-rich strand, ExoI activity will expose G-rich single-stranded gaps that can be detected in a TRF analysis in native conditions. (Right) Representative Southern blots of TRF after ExoI treatment in native and denatured conditions and quantification of telomeric ssDNA/dsDNA ratio in ExoI-treated genomic DNA. Error bars represent mean + SD from at least three independent experiments. *, P < 0.003 (Student’s t test).
Figure 4.
Figure 4.
Compromised proliferation of Ung-deficient B cells expressing AID. (A, left) Representative microscopy pictures of anaphases from CH12F3 cells expressing the HPV16 E6 and E7 oncoproteins and GFP control, Ugi, or Ugi shAID. Total DNA was stained with DAPI (shown in green). Bars, 2 µm. (Right) Mean + SD proportion of anaphases showing chromosome bridges in CH12F3 GFP and CH12F3 Ugi cells from at least three independent experiments. 50 anaphases were analyzed for each cell line per experiment. (B) Cell cycle profile analysis by BrdU incorporation and propidium iodide (PI) staining in the indicated CH12F3 cells 24 h after stimulating CSR. (C) Cell number (left) and CFSE staining (right) were used to evaluate cellular proliferation of dCH12F3 and CH12F3 Ugi cells expressing the indicated shRNAs after stimulation for CSR. Error bars represent mean + SD from at least three independent experiments. shTERT, shRNA against the telomerase reverse transcriptase (TERT).
Figure 5.
Figure 5.
Compromised clonal expansion of Ung−/− GC B cells in vivo. (A) Absolute number (left) and proportion (right) of AID-GFP+ cells in the spleen of AID-GFPtg and Ung−/− AID-GFPtg mice 8 d after immunization, as calculated from flow cytometry analyses of three independent experiments. (B) Representative confocal images of GCs in the spleen of AID-GFPtg and Ung−/− AID-GFPtg mice stained for IgD and PNA. Bars, 20 µm. (C) Quantification of GC size. Each symbol represents the median area in square inches (sq in) of all GCs observed in splenic sections from four wild-type and five Ung−/− AID-GFPtg mice coming from two of the experiments represented in A. Data are derived from three independent experiments. (D) The number of GCs per splenic section were counted in the same mice as in C. (A, C, and D) The p-values from unpaired two-tailed Student’s t tests are shown, and horizontal bars indicate median values. (E) Representative images used to measure AID-GFP+ GC number and area. Partial composite sections of immunized spleens made of multiple overlapping images obtained by spinning disk confocal microscopy are shown for each genotype. Bars, 0.25 mm.
Figure 6.
Figure 6.
The proliferation of malignant B cells expressing AID depends on UNG. (A) Incidence of spontaneous lymphoma, lymphoid hyperplasia, or any other tumor in wild-type and Ung−/− mice. The total number of mice analyzed is shown at the center of each pie. (B, top) Representative IHC pictures of AID staining in B cell lymphomas found in Ung−/− mice. Positive and negative staining controls are shown using spleen from immunized wild-type and Aicda−/− mice, respectively. (Bottom) AID status of the lymphoma cells, as judged from IHC, for each of the mice diagnosed with B cell lymphoma. Bars, 50 µm. (C) Western blot analysis of AID levels in human DLBCL cell lines and control fibroblasts (IMR90). (D) UNG activity assay in cell extracts (10 µg protein) of the indicated DLBCL cell lines using a fluorescein-labeled oligonucleotide with a single dU residue as the substrate. The reaction products resolved by TBE-urea PAGE are indicated on the left. A Western blot of γ-tubulin was used as the loading control. (E) The proliferation of the indicated human DLBCL cell lines expressing GFP control, AID, or Ugi and the indicated shRNAs was measured by growth curves. (F) Quantification of metaphases with STL in the same cell lines analyzed in E. (E and F) Data are mean + SD from three independent experiments.
Figure 7.
Figure 7.
Proposed molecular mechanism of the alternative processing of AID-induced telomeric damage in B cells. AID is induced in activated B cells and stochastically targets some telomeres, likely through association with the RPII at the subtelomeric (sub-tel.) promoter. UNG initiates error-free BER of the C-rich telomeres deaminated by AID, thereby preventing any telomeric damage and protecting cell proliferation. In UNG-deficient B cells, the uracils made by AID at telomeres are recognized instead as dG:dU mismatches by MMR and processed into a nick or short gap. This nick or short gap could stall leading strand synthesis and produce a very short telomere in one sister chromatid after replication, hampering cell proliferation potential.

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