哺乳动物细胞中DNA烷基磷酸三酯加合物的大小和立体化学依赖性转录旁路。

DNA Pub Date : 2022-12-01 DOI:10.3390/dna2040016
Ying Tan, Jiabin Wu, Garrit Clabaugh, Lin Li, Hua Du, Yinsheng Wang
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引用次数: 3

摘要

环境、内源性和治疗性烷基化剂可以与DNA中的核苷酸间磷酸基团反应生成烷基磷酸三酯(PTE)加合物。烷基pte的诱导频率相对较高,并在哺乳动物组织中持续存在;然而,它们在哺乳动物细胞中的生物学后果尚未得到检验。在此,我们评估了具有不同烷基大小和立体化学构型(Me和nPr的S P和R P非对映体)的烷基- pte如何影响哺乳动物细胞中的转录效率和保真度。我们发现,虽然Me-和npr - pte的rp非对映体分别构成中度和强烈的转录阻断,但两种病变的S P非对映体并未明显干扰转录效率。此外,四种烷基pte均未诱导突变体转录本。此外,聚合酶η在促进S - P-Me-PTE的转录中发挥了重要作用,但在其他三种病变中没有作用。其他翻译合成(TLS)聚合酶的缺失,包括Pol κ、Pol ι、Pol ξ和REV1,没有改变任何烷基pte病变的转录旁路效率或突变频率。总之,我们的研究为烷基- pte损伤对转录的影响提供了重要的新知识,并扩大了转录旁路中Pol η的底物池。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Size- and Stereochemistry-Dependent Transcriptional Bypass of DNA Alkyl Phosphotriester Adducts in Mammalian Cells.

Environmental, endogenous and therapeutic alkylating agents can react with internucleotide phosphate groups in DNA to yield alkyl phosphotriester (PTE) adducts. Alkyl-PTEs are induced at relatively high frequencies and are persistent in mammalian tissues; however, their biological consequences in mammalian cells have not been examined. Herein, we assessed how alkyl-PTEs with different alkyl group sizes and stereochemical configurations (S P and R P diastereomers of Me and nPr) affect the efficiency and fidelity of transcription in mammalian cells. We found that, while the R P diastereomer of Me- and nPr-PTEs constituted moderate and strong blockages to transcription, respectively, the S P diastereomer of the two lesions did not appreciably perturb transcription efficiency. In addition, none of the four alkyl-PTEs induced mutant transcripts. Furthermore, polymerase η assumed an important role in promoting transcription across the S P-Me-PTE, but not any of other three lesions. Loss of other translesion synthesis (TLS) polymerases tested, including Pol κ, Pol ι, Pol ξ and REV1, did not alter the transcription bypass efficiency or mutation frequency for any of the alkyl-PTE lesions. Together, our study provided important new knowledge about the impact of alkyl-PTE lesions on transcription and expanded the substrate pool of Pol η in transcriptional bypass.

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DNA
DNA
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