Checkpoint kinase 1 negatively regulates somatic hypermutation
Checkpoint kinase 1 negatively regulates somatic hypermutation
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DOI：
10.1093/nar/gkt1378
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发表时间：
2014-04-01
影响因子：
14.9
通讯作者：
Jungnickel, Berit
中科院分区：
文献类型：
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作者：
Frankenberger, Samantha;Davari, Kathrin;Jungnickel, Berit
生发中心B细胞的体细胞超突变使免疫球蛋白(Ig)多样化，有助于体液免疫反应的成熟，但也存在过度或异常基因改变的风险。因此，在生发中心的反应中，需要严格调控由激活诱导的胞苷脱氨酶引起的DNA损伤以及由多个途径引起的DNA修复，以防止淋巴瘤的发生。在本研究中，我们发现DNA损伤检查点信号通过检查点蛋白1(Chk1)负向调节体细胞的超突变。人B细胞淋巴瘤细胞系中Chk1的抑制以及DT40B细胞中Chk1等位基因的失活会导致体细胞过度突变的增加。这显然是由于Chk1调控的DNA修复途径发生了变化，例如同源重组效率降低，这也导致了DT40中Ig基因转化的降低。我们的数据表明，Chk1信号在免疫球蛋白多样化的调节中起着至关重要的作用，并为B细胞淋巴瘤中异常体细胞过度突变的潜在来源提供了意想不到的线索。
Immunoglobulin (Ig) diversification by somatic hypermutation in germinal center B cells is instrumental for maturation of the humoral immune response, but also bears the risk of excessive or aberrant genetic changes. Thus, introduction of DNA damage by activation-induced cytidine deaminase as well as DNA repair by multiple pathways need to be tightly regulated during the germinal center response to prevent lymphomagenesis. In the present study, we show that DNA damage checkpoint signaling via checkpoint kinase 1 (Chk1) negatively regulates somatic hypermutation. Chk1 inhibition in human B cell lymphoma lines as well as inactivation of Chk1 alleles by gene targeting in DT40 B cells leads to increased somatic hypermutation. This is apparently due to changes in DNA repair pathways regulated by Chk1, such as a decreased homologous recombination efficiency that also leads to decreased Ig gene conversion in DT40. Our data show that Chk1 signaling plays a crucial role in regulation of Ig diversification and sheds unexpected light on potential origins of aberrant somatic hypermutation in B cell lymphomagenesis.