维持的抗体去氨酶APOBEC3A（A3A）和APOBEC3B（A3B）能够显着引发人类癌症基因组的突变。然而，APOBEC诱导的突变的肿瘤特异性遗传调节因子并未得到明确定义。在这里，我们利用筛选的方法，鉴定了61个基因缺失增加酵母中A3B诱导突变的基因缺失。我们还确定了每个基因缺失是否与Ung1的丧失有上位效应，以判断编码因子是否参与到A3B/Ung1依赖非常规富含法A3B催化反应，从而产生的单链DNA (ssDNA) 导致A3B/Ung1依赖非常规富含的绕雇与HR依赖的趋过程的减少。我们发现A3B诱导突变的突变谱表明了基因型特异的單链DNA形成和結合方式突變靶（APOBEC诱导的病变）的。结合这三种指标，我们能够建立一种多因素的APOBEC诱导突变的特征，即 (1) 阻断H3K56乙酰化的感受性，(2) 功能缺陷的CTF18-RFC复合物，(3) HR依赖的APOBEC诱导病变绕过。我们通过分析人类肿瘤突变数据来扩展这些结果，发现BRCA1/2缺乏的乳腺癌显示了APOBEC诱导突变的3至4倍增加。在酵母中，镜像我们的结果，Rev1介导的C到G的替代主要负责BRCA1/2缺乏肿瘤中APOBEC特定突变的增加，并且这些突变与复制过程中的落后链合成相关。这些结果鉴定了在DNA复制动力学上起重要作用的因子，并可能影响肿瘤进展过程中APOBEC诱导突变的丰度。他们还强调了BRCA1/2在依赖HR的APOBEC诱导病变趋过过程中在癌细胞复制过程中的新角色。冷泉港实验室出版。

The cytidine deaminases APOBEC3A (A3A) and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we utilized a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast. We also determined whether each deletion was epistatic with Ung1 loss, which indicated whether the encoded factors participate in the HR-dependent bypass of A3B/Ung1-dependent abasic sites or suppress A3B-catalyzed deamination by protecting against aberrant formation of single stranded DNA (ssDNA). We found that the mutation spectra of A3B-induced mutations revealed genotype-specific patterns of strand-specific ssDNA formation and nucleotide incorporation across APOBEC-induced lesions. Combining these three metrics, we were able to establish a multifactorial signature of APOBEC-induced mutations specific to (1) failure to remove H3K56 acetylation, (2) defective CTF18-RFC complex function, and (3) defective HR-mediated bypass of APOBEC-induced lesions. We extended these results by analyzing mutation data for human tumors and found BRCA1/2-deficient breast cancers display 3- to 4-fold more APOBEC-induced mutations. Mirroring our results in yeast, Rev1-mediated C-to-G substitutions are mainly responsible for increased APOBEC-signature mutations in BRCA1/2-deficient tumors, and these mutations associate with lagging strand synthesis during replication. These results identify important factors that influence DNA replication-dynamics and likely the abundance of APOBEC-induced mutation during tumor progression. They also highlight a novel role for BRCA1/2 during HR-dependent lesion bypass of APOBEC-induced lesions during cancer cell replication.Published by Cold Spring Harbor Laboratory Press.