Apurinic/apyrimidinic endonuclease 2 regulates the expansion of germinal centers by protecting against activation-induced cytidine deaminase-independent DNA damage in B cells.
Apurinic/apyrimidinic endonuclease 2 regulates the expansion of germinal centers by protecting against activation-induced cytidine deaminase-independent DNA damage in B cells.
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DOI：
10.4049/jimmunol.1400002
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发表时间：
2014-07-15
期刊：
影响因子：
--
通讯作者：
Schrader CE
中科院分区：
文献类型：
--
作者：
Guikema JE;Linehan EK;Esa N;Tsuchimoto D;Nakabeppu Y;Woodland RT;Schrader CE
激活诱导的胞苷脱氨酶（AID 3）启动在生发中心（GC）B细胞中产生DNA突变和断裂的过程，所述DNA突变和断裂是体细胞超突变和类别转换重组所必需的。GC B细胞可以“耐受”DNA损伤，同时由于BCL 6对DNA损伤反应的部分抑制而快速增殖。在这里，我们建立了一个模型来研究小鼠GC B细胞对内源性DNA损伤的反应。我们发现，碱基切除修复蛋白脱嘌呤/脱嘧啶核酸内切酶2（APE 2）在体外保护活化的B细胞免受氧化损伤。与野生型小鼠相比，APE 2缺陷型小鼠具有较小的生发中心和降低的抗体反应。在APE 2缺陷小鼠快速分裂的GC中心母细胞中，DNA双链断裂增加，这激活了p53非依赖性细胞周期检查点和p53依赖性凋亡反应。在WT、AID和APE 2缺陷小鼠中，代谢性和/或氧化性损伤和AID依赖性损伤是与GC大小呈负相关的加性应激。过量的DSB导致BCL 6的表达降低，这将使DNA修复途径成为可能，但限制GC细胞数量。这些结果描述了APE 2在保护GC细胞免受艾滋病非依赖性损伤中的非冗余作用，尽管GC细胞独特地耐受DNA损伤，但我们发现DNA损伤反应仍然可以通过涉及p53和BCL 6的途径调节GC大小。
Activation-induced cytidine deaminase (AID3) initiates a process generating DNA mutations and breaks in germinal center (GC) B cells that are necessary for somatic hypermutation and class switch recombination. GC B cells can “tolerate” DNA damage while rapidly proliferating due to partial suppression of the DNA damage response by BCL6. Here, we develop a model to study the response of mouse GC B cells to endogenous DNA damage. We show that the base excision repair protein apurinic/apyrimidinic endonuclease 2 (APE2) protects activated B cells from oxidative damage in vitro. APE2-deficient mice have smaller germinal centers and reduced antibody responses compared to wild-type mice. DNA double-strand breaks are increased in the rapidly dividing GC centroblasts of APE2-deficient mice, which activate a p53-independent cell-cycle checkpoint and a p53-dependent apoptotic response. Proliferative and/or oxidative damage and AID-dependent damage are additive stresses that correlate inversely with GC size in WT, AID- and APE2-deficient mice. Excessive DSBs lead to decreased expression of BCL6, which would enable DNA repair pathways but limit GC cell numbers. These results describe a non-redundant role for APE2 in the protection of GC cells from AID-independent damage and, although GC cells uniquely tolerate DNA damage, we find that the DNA damage response can still regulate GC size through pathways that involve p53 and BCL6.
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DOI：
10.1126/science.1213368
发表时间：
2012-06-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Khalil AM;Cambier JC;Shlomchik MJ
通讯作者：
Shlomchik MJ
影响因子：
5.3
作者：
Masani, Shahnaz;Han, Li;Yu, Kefei
通讯作者：
Yu, Kefei
DOI：
10.1073/pnas.0505949102
发表时间：
2005-12-20
影响因子：
11.1
作者：
Garg, P;Burgers, PM
通讯作者：
Burgers, PM
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
15.3
作者：
Guikema, Jeroen E. J.;Linehan, Erin K.;Schrader, Carol E.
通讯作者：
Schrader, Carol E.