文章：

失调的APOBEC3G引发DNA损伤并促进多发性骨髓瘤中的基因组不稳定性

Dysregulated APOBEC3G causes DNA damage and promotes genomic instability in multiple myeloma

原文发布日期：2021-10-08

DOI: 10.1038/s41408-021-00554-9

类型: Article

开放获取: 是

英文摘要：

Multiple myeloma (MM) is a heterogeneous disease characterized by significant genomic instability. Recently, a causal role for the AID/APOBEC deaminases in inducing somatic mutations in myeloma has been reported. We have identified APOBEC/AID as a prominent mutational signature at diagnosis with further increase at relapse in MM. In this study, we identified upregulation of several members of APOBEC3 family (A3A, A3B, A3C, and A3G) with A3G, as one of the most expressed APOBECs. We investigated the role of APOBEC3G in MM and observed that A3G expression and APOBEC deaminase activity is elevated in myeloma cell lines and patient samples. Loss-of and gain-of function studies demonstrated that APOBEC3G significantly contributes to increase in DNA damage (abasic sites and DNA breaks) in MM cells. Evaluation of the impact on genome stability, using SNP arrays and whole genome sequencing, indicated that elevated APOBEC3G contributes to ongoing acquisition of both the copy number and mutational changes in MM cells over time. Elevated APOBEC3G also contributed to increased homologous recombination activity, a mechanism that can utilize increased DNA breaks to mediate genomic rearrangements in cancer cells. These data identify APOBEC3G as a novel gene impacting genomic evolution and underlying mechanisms in MM.
 

摘要翻译： 

多发性骨髓瘤（MM）是一种具有显著基因组不稳定性的异质性疾病。近期研究报道，AID/APOBEC脱氨酶家族在多发性骨髓瘤体细胞突变的发生中具有因果作用。我们发现在MM初诊时APOBEC/AID已成为重要的突变特征，且在复发时进一步增加。本研究中，我们鉴定出APOBEC3家族多个成员（A3A、A3B、A3C和A3G）的表达上调，其中A3G是表达量最高的APOBEC蛋白之一。通过研究APOBEC3G在MM中的作用，我们观察到骨髓瘤细胞系和患者样本中A3G表达及APOBEC脱氨酶活性均显著升高。功能缺失与功能获得实验证明，APOBEC3G会明显增加MM细胞中的DNA损伤（脱碱基位点与DNA断裂）。通过SNP芯片和全基因组测序评估其对基因组稳定性的影响，发现APOBEC3G的持续高表达会促进MM细胞随时间不断累积拷贝数变异和突变。APOBEC3G的升高还会增强同源重组活性，该机制可利用增加的DNA断裂介导癌细胞基因组重排。这些数据证实APOBEC3G是影响多发性骨髓瘤基因组演化及其潜在机制的新关键基因。

原文链接：

Dysregulated APOBEC3G causes DNA damage and promotes genomic instability in multiple myeloma