Genetic inhibitors of APOBEC3B-induced mutagenesis.
Genetic inhibitors of APOBEC3B-induced mutagenesis.
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DOI：
10.1101/gr.277430.122
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发表时间：
2023-09
期刊：
影响因子：
7
通讯作者：
Roberts, Steven A.
中科院分区：
文献类型：
--
作者：
Mertz, Tony M.;Rice-Reynolds, Elizabeth;Nguyen, Ly;Wood, Anna;Cordero, Cameron;Bray, Nicholas;Harcy, Victoria;Vyas, Rudri K.;Mitchell, Debra;Lobachev, Kirill;Roberts, Steven A.
胞苷脱氨酶 APOBEC3A (A3A) 和 APOBEC3B (A3B) 是人类癌症基因组的重要突变体。然而，APOBEC 诱导突变的肿瘤特异性遗传调节剂尚不清楚。在这里，我们使用筛选来识别 61 个基因缺失，这些缺失会增加酵母中 A3B 诱导的突变。我们还确定了每个缺失是否随 Ung1 丢失而上位，这表明编码因子是否参与 A3B/Ung1 依赖的无碱基位点的同源重组 (HR) 依赖旁路，或通过防止单链 DNA (ssDNA) 的异常形成来抑制 A3B 催化的脱氨作用。我们发现 A3B 诱导突变的突变谱揭示了 APOBEC 诱导病变中链特异性 ssDNA 形成和核苷酸掺入的基因型特异性模式。结合这三个指标，我们能够建立 APOBEC 诱导突变的多因素特征，这些突变特异于 (1) 未能去除 H3K56 乙酰化，(2) CTF18-RFC 复合体功能缺陷，以及 (3) HR 介导的 APOBEC 诱导病变旁路缺陷。我们通过分析人类肿瘤的突变数据扩展了这些结果，发现 BRCA1/2 缺陷的乳腺癌显示出 APOBEC 诱导的突变多出三到四倍。与我们在酵母中的结果一致，Rev1 介导的 C 至 G 取代主要是 BRCA1/2 缺陷肿瘤中 APOBEC 特征突变增加的主要原因，并且这些突变与复制过程中的滞后链合成相关。这些结果确定了影响 DNA 复制动态的重要因素以及肿瘤进展过程中 APOBEC 诱导突变的丰度。他们还强调了 BRCA1/2 在癌细胞复制过程中 APOBEC 诱导病变的 HR 依赖性病变旁路过程中的新作用。
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 used 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 homologous recombination (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 three- to fourfold 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.
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影响因子：
30.8
作者：
Burns, Michael B.;Temiz, Nuri A.;Harris, Reuben S.
通讯作者：
Harris, Reuben S.
DOI：
10.1097/igc.0000000000000681
发表时间：
2016-06
期刊：
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
影响因子：
--
作者：
Billingsley CC;Cohn DE;Mutch DG;Hade EM;Goodfellow PJ
通讯作者：
Goodfellow PJ
DOI：
10.1126/science.1135862
发表时间：
2007-02-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Driscoll R;Hudson A;Jackson SP
通讯作者：
Jackson SP
DOI：
10.1016/j.mrfmmm.2015.01.005
发表时间：
2015-06
影响因子：
2.3
作者：
Zhu, Qianzheng;Battu, Aruna;Ray, Alo;Wani, Gulzar;Qian, Jiang;He, Jinshan;Wang, Qi-en;Wani, Altaf A.
通讯作者：
Wani, Altaf A.
影响因子：
4.5
作者：
Gershon L;Kupiec M
通讯作者：
Kupiec M