Department of Epigenetics & Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78507, USA; The University of Texas MD Anderson Cancer Center, UT Health Graduate School of Biomedical Sciences, Houston, TX, USA.
Department of Epigenetics & Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78507, USA.
Cell Rep. 2021 Feb 23;34(8):108775. doi: 10.1016/j.celrep.2021.108775.
In mammalian cells, specialized DNA polymerase ζ (pol ζ) contributes to genomic stability during normal DNA replication. Disruption of the catalytic subunit Rev3l is toxic and results in constitutive chromosome damage, including micronuclei. As manifestations of this genomic stress are unknown, we examined the transcriptome of pol ζ-defective cells by RNA sequencing (RNA-seq). Expression of 1,117 transcripts is altered by ≥4-fold in Rev3l-disrupted cells, with a pattern consistent with an induction of an innate immune response. Increased expression of interferon-stimulated genes at the mRNA and protein levels in pol ζ-defective cells is driven by the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-signaling partner stimulator of interferon genes (STING) pathway. Expression of key interferon-stimulated chemokines is elevated in basal epithelial mouse skin cells with a disruption of Rev3l. These results indicate that the disruption of pol ζ may simultaneously increase sensitivity to genotoxins and potentially engage parts of the innate immune response, which could add an additional benefit to targeting pol ζ in cancer therapies.
在哺乳动物细胞中，专门的 DNA 聚合酶 ζ（pol ζ）有助于在正常 DNA 复制过程中维持基因组稳定性。催化亚基 Rev3l 的破坏是有毒的，并导致持续的染色体损伤，包括微核。由于这种基因组应激的表现尚不清楚，我们通过 RNA 测序（RNA-seq）检查了 pol ζ 缺陷细胞的转录组。Rev3l 缺失细胞中 1117 个转录本的表达至少增加了 4 倍，其模式与先天免疫反应的诱导一致。pol ζ 缺陷细胞中干扰素刺激基因的 mRNA 和蛋白质水平的表达增加是由环鸟苷酸-腺苷酸单磷酸合酶（cGAS）-干扰素基因刺激物（STING）途径的信号伴侣驱动的。Rev3l 破坏后，基础上皮小鼠皮肤细胞中关键干扰素刺激趋化因子的表达升高。这些结果表明，pol ζ 的破坏可能同时增加对遗传毒性物质的敏感性，并可能激活先天免疫反应的部分反应，这可能为癌症治疗中靶向 pol ζ 提供额外的益处。
