AID-dependent somatic hypermutation occurs as a DNA single-strand event in the BL2 cell line

Faili, Ahmad; Aoufouchi, Saïd; Guéranger, Quentin; Zober, Carole; Léon, Anne; Bertocci, Barbara; Weill, Jean‐Claude; Reynaud, Claude‐Agnès

doi:10.1038/ni826

Cited by 166 publications

(147 citation statements)

References 42 publications

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“…Human Burkitt's lymphomas undergo SHM in culture either constitutively (Ramos cell line) or after induction (BL2 or CL-01 cell lines) [81][82][83][84] . The pattern of mutations does not mimic the SHM pattern generated in vivo as it displays more mutations at G/C base pairs (80% versus 20% at A/T base pairs).…”

Section: Polη the Study Of Patients Affected By The Xeroderma Pigmenmentioning

confidence: 99%

DNA polymerases in adaptive immunity

Weill

Reynaud

2008

Nat Rev Immunol

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PrefaceTo cope with an unpredictable variety of potential pathogenic insults, the immune system must generate an enormous diversity of recognition structures, and it does so by making stepwise modifications of key genetic loci in each lymphoid cell. This proceeds through the action of lymphoid-specific proteins acting together with the general DNA-repair machinery of the cell. Strikingly, these general mechanisms are usually diverted from their normal functions, being used in rather atypical ways in order to privilege diversity over accuracy. In this Review, we focus on the contribution of a set of DNA polymerases discovered in the last decade to these unique DNA transactions.

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Section: Polη the Study Of Patients Affected By The Xeroderma Pigmenmentioning

confidence: 99%

DNA polymerases in adaptive immunity

Weill

Reynaud

2008

Nat Rev Immunol

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“…The mutational process was activated in vivo by the combined crosslinking of surface immunoglobulin with CD19/CD21 receptors [23]. Cells (2 × 10 6 ) were incubated with 4 μl of biotinylated anti-human IgM (Pharmingen, San Diego, CA), 20 μl of anti-human CD19 (Southern Biotech., Birmingham, AL), 40 μl of phycoerythrin-anti-CD21 (Pharmingen) in 500 μl of RPMI medium for 20 min at 4 °C.…”

Section: Mutagenesis In B Cellsmentioning

confidence: 99%

Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell lines

et al. 2007

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Somatic hypermutation (SHM) is a fundamental process in immunoglobulin gene maturation that results in increased affinity of antibodies toward antigens. In one hypothesis explaining SHM in human B cells, the process is initiated by enzymatic deamination of cytosine to uracil in the immunoglobulin gene V-region and this in turn triggers mutation-prone forms of uracil-DNA base excision repair (BER). Yet, an uncertainty with this model is that BER of uracil-DNA in mammalian cells is generally error-free, wherein DNA polymerase β (pol β) conducts gap-filling synthesis by insertion of bases according to Watson-Crick rules. To evaluate this inconsistency, we examined pol β expression in various SHM proficient human BL2 cell line subclones. We report that expression of pol β in SHM proficient cell lines was strongly down-regulated. In contrast, in other BL2 subclones, we found that SHM was deficient and that pol β expression was much higher than in the SHM proficient subclones. We also found that overexpression of recombinant human pol β in a SHM proficient subclone abrogated its capacity for SHM. These results suggest that down-regulation of the normal BER gap-filling DNA polymerase, pol β, accompanies induced SHM in BL2 cells. This is consistent with the hypothesis that normal error-free BER must be silenced to make way for an error-prone BER process that may be required during somatic hypermutation.

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“…Cette cassure double-brins est soit « primitive », soit la résultante de cassures « simplebrin » situées sur les deux brins de l'ADN. Plusieurs groupes ont récem-ment décrit la formation de cassures double-brins de l'ADN dans les Deux ans après, l'activationinduced cytidine deaminase n'a pas livré tous ses secrets régions V au cours de la création des mutations somatiques [5][6][7][8], mais ces observations sont de plus en plus controversées et apparaissent non spécifiques [7,9]. Or, les foyers de réparation des cassures de l'ADN comprenant l'histone H2AX phosphorylée et la protéine de réparation nibrine, qui sont normalement présentes dans les régions S au cours de la commutation isotypique, ne sont pas détectés dans des lymphocytes B de souris déficientes en AID [10].…”

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