Hypomorphic mutation in the large subunit of replication protein A affects mutagenesis by human APOBEC cytidine deaminases in yeast.

IF 2.1 3区 生物学 Q3 GENETICS & HEREDITY G3: Genes|Genomes|Genetics Pub Date : 2024-10-07 DOI:10.1093/g3journal/jkae196
Matthew S Dennen, Zachary W Kockler, Steven A Roberts, Adam B Burkholder, Leszek J Klimczak, Dmitry A Gordenin
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Abstract

Human APOBEC single-strand (ss) specific DNA and RNA cytidine deaminases change cytosines to uracils (U's) and function in antiviral innate immunity and RNA editing and can cause hypermutation in chromosomes. The resulting U's can be directly replicated, resulting in C to T mutations, or U-DNA glycosylase can convert the U's to abasic (AP) sites which are then fixed as C to T or C to G mutations by translesion DNA polymerases. We noticed that in yeast and in human cancers, contributions of C to T and C to G mutations depend on the origin of ssDNA mutagenized by APOBECs. Since ssDNA in eukaryotic genomes readily binds to replication protein A (RPA) we asked if RPA could affect APOBEC-induced mutation spectrum in yeast. For that purpose, we expressed human APOBECs in the wild-type (WT) yeast and in strains carrying a hypomorph mutation rfa1-t33 in the large RPA subunit. We confirmed that the rfa1-t33 allele can facilitate mutagenesis by APOBECs. We also found that the rfa1-t33 mutation changed the ratio of APOBEC3A-induced T to C and T to G mutations in replicating yeast to resemble a ratio observed in long persistent ssDNA in yeast and in cancers. We present the data suggesting that RPA may shield APOBEC formed U's in ssDNA from Ung1, thereby facilitating C to T mutagenesis through the accurate copying of U's by replicative DNA polymerases. Unexpectedly, we also found that for U's shielded from Ung1 by WT RPA, the mutagenic outcome is reduced in the presence of translesion DNA polymerase zeta.

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复制蛋白 A 大亚基的畸形突变会影响酵母中人类 APOBEC 胞苷脱氨酶的诱变作用。
人类 APOBEC 单链(ss)特异性 DNA 和 RNA 胞苷脱氨酶可将胞嘧啶变为尿嘧啶,在抗病毒先天免疫、RNA 编辑中发挥作用,并可导致染色体的超突变。由此产生的尿嘧啶可以直接复制,导致 C 到 T 的突变,或者尿嘧啶-DNA 糖基化酶可以将尿嘧啶转化为消旋(AP)位点,然后通过转座 DNA 聚合酶固定为 C 到 T 或 C 到 G 的突变。我们注意到,在酵母和人类癌症中,C 到 T 和 C 到 G 突变的贡献率取决于被 APOBECs 诱导突变的 ssDNA 的来源。由于真核生物基因组中的ssDNA很容易与复制蛋白A(RPA)结合,我们询问RPA是否会影响酵母中APOBEC诱导的突变谱。为此,我们在野生型酵母和携带大 RPA 亚基低位突变 rfa1-t33 的菌株中表达了人类 APOBEC。我们证实 rfa1-t33 等位基因能促进 APOBECs 的诱变作用。我们还发现,在复制酵母中,rfa1-t33 突变改变了 APOBEC3A 诱导的 T 到 C 突变和 T 到 G 突变的比例,使其类似于在酵母和癌症中长期存在的 ssDNA 中观察到的比例。我们提供的数据表明,RPA 可能会保护 ssDNA 中 APOBEC 形成的尿嘧啶不受 Ung1 的影响,从而通过复制 DNA 聚合酶对尿嘧啶的精确复制,促进 C 到 T 的突变。意想不到的是,我们还发现,对于被野生型 RPA 从 Ung1 中屏蔽掉的尿嘧啶,在存在转座 DNA 聚合酶 zeta 的情况下,诱变结果会降低。
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来源期刊
G3: Genes|Genomes|Genetics
G3: Genes|Genomes|Genetics GENETICS & HEREDITY-
CiteScore
5.10
自引率
3.80%
发文量
305
审稿时长
3-8 weeks
期刊介绍: G3: Genes, Genomes, Genetics provides a forum for the publication of high‐quality foundational research, particularly research that generates useful genetic and genomic information such as genome maps, single gene studies, genome‐wide association and QTL studies, as well as genome reports, mutant screens, and advances in methods and technology. The Editorial Board of G3 believes that rapid dissemination of these data is the necessary foundation for analysis that leads to mechanistic insights. G3, published by the Genetics Society of America, meets the critical and growing need of the genetics community for rapid review and publication of important results in all areas of genetics. G3 offers the opportunity to publish the puzzling finding or to present unpublished results that may not have been submitted for review and publication due to a perceived lack of a potential high-impact finding. G3 has earned the DOAJ Seal, which is a mark of certification for open access journals, awarded by DOAJ to journals that achieve a high level of openness, adhere to Best Practice and high publishing standards.
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