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PARP1 Is Required for ATM-Mediated p53 Activation and p53-Mediated Gene Expression after Ionizing Radiation.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-06-19 , DOI: 10.1021/acs.chemrestox.0c00130 Sabine Gajewski 1 , Andrea Hartwig 1
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-06-19 , DOI: 10.1021/acs.chemrestox.0c00130 Sabine Gajewski 1 , Andrea Hartwig 1
Affiliation
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PARP1 and p53 are key players in maintaining genomic stability, but their interplay is still not fully understood. We investigated the impact of PARP1 knockout on the DNA damage response after ionizing radiation (IR) by comparing a U2OS-based PARP1-knockout cell line, established by using the genome-editing system CRISPR/Cas9, with its wild-type counterpart. We intended to gain more insight into the impact of PARP1 on the transcriptional level under basal conditions, after low dose (1 Gy) and high dose (10 Gy) DNA damage induced by IR, aiming to reveal the potential connections between the involved pathways. In the absence of additionally induced DNA damage, lacking PARP1 led to an increased up-regulation of CDKN1A (p21), which caused a G1 arrest and slightly diminished cell proliferation. While a small but comparable transcriptional DNA damage response was observed upon 1 Gy IR in both cell lines, a pronounced transcriptional induction of p53 target genes was evident after treatment with 10 Gy IR exclusively in PARP1-proficient cells, suggesting that PARP1 facilitates the p53 signaling response after IR. Additionally, PARP1 appeared to be required for the ATM-dependent activation of PLK3, which in turn activates p53, leading to its transcriptional damage response. Our results support the involvement of PARP1 activation among the first steps in IR-induced DNA damage response.
中文翻译：
电离辐射后，ATM介导的p53激活和p53介导的基因表达需要PARP1。
PARP1和p53是维持基因组稳定性的关键因素，但它们之间的相互作用仍不完全清楚。通过比较使用基因组编辑系统CRISPR / Cas9建立的基于U2OS的PARP1敲除细胞系及其野生型对应物，我们研究了电离辐射（IR）后PARP1敲除对DNA损伤响应的影响。我们打算在基础条件下，在IR引起的低剂量（1 Gy）和高剂量（10 Gy）DNA损伤后，深入了解PARP1对转录水平的影响，旨在揭示所涉及途径之间的潜在联系。在不存在额外诱导的DNA损伤的情况下，缺乏PARP1会导致CDKN1A（p21）的上调增加，从而导致G 1阻止并略微减少细胞增殖。虽然在两种细胞系中均以1 Gy IR观察到较小但可比的转录DNA损伤反应，但仅在PARP1熟练的细胞中仅用10 Gy IR处理后，p53靶基因的明显转录诱导明显出现，表明PARP1促进了p53信号IR后的反应。此外，PARP1似乎是依赖ATM的PLK3激活所必需的，PLK3继而激活p53，从而导致其转录损伤应答。我们的结果支持PARP1激活参与IR诱导的DNA损伤反应的第一步。
更新日期：2020-07-20
中文翻译：
电离辐射后，ATM介导的p53激活和p53介导的基因表达需要PARP1。
PARP1和p53是维持基因组稳定性的关键因素，但它们之间的相互作用仍不完全清楚。通过比较使用基因组编辑系统CRISPR / Cas9建立的基于U2OS的PARP1敲除细胞系及其野生型对应物，我们研究了电离辐射（IR）后PARP1敲除对DNA损伤响应的影响。我们打算在基础条件下，在IR引起的低剂量（1 Gy）和高剂量（10 Gy）DNA损伤后，深入了解PARP1对转录水平的影响，旨在揭示所涉及途径之间的潜在联系。在不存在额外诱导的DNA损伤的情况下，缺乏PARP1会导致CDKN1A（p21）的上调增加，从而导致G 1阻止并略微减少细胞增殖。虽然在两种细胞系中均以1 Gy IR观察到较小但可比的转录DNA损伤反应，但仅在PARP1熟练的细胞中仅用10 Gy IR处理后，p53靶基因的明显转录诱导明显出现，表明PARP1促进了p53信号IR后的反应。此外，PARP1似乎是依赖ATM的PLK3激活所必需的，PLK3继而激活p53，从而导致其转录损伤应答。我们的结果支持PARP1激活参与IR诱导的DNA损伤反应的第一步。
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