Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A.

中文翻译：

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SMC5/6 复合物可防止 APOBEC3A 介导的复制应激下的遗传毒性。


由 APOBEC3胞苷脱氨酶活性引起的突变模式在整个人类癌症基因组中都很明显。特别是，APOBEC3A家族成员是一种强效基因毒素，可在实验系统和人类肿瘤中造成大量 DNA 损伤。然而，确保具有活性 APOBEC3A 的细胞中基因组稳定性的机制尚不清楚。通过无偏倚的全基因组筛选，我们将染色体 5/6 的结构维护 （SMC5/6） 复合物定义为 APOBEC3A 活跃时对细胞活力至关重要。我们观察到 SMC5/6 功能障碍的人肿瘤中没有 APOBEC3A 诱变，这与合成致死性一致。在 DNA 复制过程中，耗尽 SMC5/6 的癌细胞会因 APOBEC3A 活性而造成严重的基因组损伤。此外，APOBEC3A活性导致复制束延长，这取决于 PrimPol，这与 APOBEC3A 诱导损伤下游 DNA 合成的重新开始一致。SMC5/6 的缺失会消除伸长的复制束，并在 APOBEC3A 活性时增加 DNA 断裂。我们的研究结果表明，复制叉延长反映了 DNA 损伤对 APOBEC3A 活性的损伤反应，该活性以 SMC5/6 依赖性方式促进基因组稳定性。因此，SMC5/6 在具有活动性 APOBEC3A 的肿瘤中表现出潜在的治疗脆弱性。