Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.
Cell Rep. 2022 Mar 22;38(12):110555. doi: 10.1016/j.celrep.2022.110555.
Mutational signatures defined by single base substitution (SBS) patterns in cancer have elucidated potential mutagenic processes that contribute to malignancy. Two prevalent mutational patterns in human cancers are attributed to the APOBEC3 cytidine deaminase enzymes. Among the seven human APOBEC3 proteins, APOBEC3A is a potent deaminase and proposed driver of cancer mutagenesis. In this study, we prospectively examine genome-wide aberrations by expressing human APOBEC3A in avian DT40 cells. From whole-genome sequencing, we detect hundreds to thousands of base substitutions per genome. The APOBEC3A signature includes widespread cytidine mutations and a unique insertion-deletion (indel) signature consisting largely of cytidine deletions. This multi-dimensional APOBEC3A signature is prevalent in human cancer genomes. Our data further reveal replication-associated mutations, the rate of stem-loop and clustered mutations, and deamination of methylated cytidines. This comprehensive signature of APOBEC3A mutagenesis is a tool for future studies and a potential biomarker for APOBEC3 activity in cancer.
癌症中单碱基替换 (SBS) 模式定义的突变特征阐明了导致恶性肿瘤的潜在诱变过程。两种在人类癌症中普遍存在的突变模式归因于 APOBEC3 胞嘧啶脱氨酶酶。在七种人类 APOBEC3 蛋白中，APOBEC3A 是一种有效的脱氨酶，被认为是癌症诱变的驱动因素。在这项研究中，我们通过在禽类 DT40 细胞中表达人类 APOBEC3A 来前瞻性地检查全基因组的异常。通过全基因组测序，我们检测到每个基因组中有数百到数千个碱基替换。APOBEC3A 特征包括广泛的胞嘧啶突变和一个独特的插入-缺失 (indel) 特征，主要由胞嘧啶缺失组成。这种多维的 APOBEC3A 特征在人类癌症基因组中很普遍。我们的数据还揭示了复制相关的突变、茎环和簇状突变的发生率以及甲基化胞嘧啶的脱氨酶。APOBEC3A 诱变的这种综合特征是未来研究的工具，也是癌症中 APOBEC3 活性的潜在生物标志物。
