Nuclear myosin 1 activates p21 gene transcription in response to DNA damage through a chromatin-based mechanism
Nuclear myosin 1 activates p21 gene transcription in response to DNA damage through a chromatin-based mechanism
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DOI：
10.1038/s42003-020-0836-1
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发表时间：
2020-03-11
影响因子：
5.9
通讯作者：
Percipalle, Piergiorgio
中科院分区：
文献类型：
--
作者：
Venit, Tomas;Semesta, Khairunnisa;Percipalle, Piergiorgio
核肌球蛋白 1 (NM1) 与关键的核功能有关。它与肌动蛋白一起被证明可以启动和调节转录，它是染色质重塑复合物 B-WICH 的一部分，负责染色体区域的重排以响应外部刺激。在这里，我们发现小鼠胚胎成纤维细胞中 NM1 的缺失会导致染色质和转录失调，从而影响 DNA 损伤和细胞周期基因的表达。 NM1 KO 细胞表现出 DNA 损伤增加以及细胞周期进程、增殖和凋亡的变化，与 p53 信号传导受损导致的表型相一致。我们发现，DNA 损伤后，NM1 与 p53 形成复合物，并通过 PCAF 和 Set1 募集至其启动子以进行组蛋白 H3 乙酰化和甲基化，从而激活检查点调节因子 p21 (Cdkn1A) 的表达。我们提出 NM1 在 DNA 损伤反应的转录反应和维持基因组稳定性中的作用。 Venit 等人。通过染色质重塑影响 p53 靶标 p21 的表达，证明核肌球蛋白 1 (NM1) 在 DNA 损伤反应中的作用。他们使用来自小鼠模型的胚胎成纤维细胞、高内涵表型分析和细胞测定、RNA-Seq 和 ChIP-Seq 以及 Pull-down 测定，结果表明，NM1 是响应依托泊苷而将 PCAF 和 SET1 招募到 p21 基因所必需的。
Nuclear myosin 1 (NM1) has been implicated in key nuclear functions. Together with actin, it has been shown to initiate and regulate transcription, it is part of the chromatin remodeling complex B-WICH, and is responsible for rearrangements of chromosomal territories in response to external stimuli. Here we show that deletion of NM1 in mouse embryonic fibroblasts leads to chromatin and transcription dysregulation affecting the expression of DNA damage and cell cycle genes. NM1 KO cells exhibit increased DNA damage and changes in cell cycle progression, proliferation, and apoptosis, compatible with a phenotype resulting from impaired p53 signaling. We show that upon DNA damage, NM1 forms a complex with p53 and activates the expression of checkpoint regulator p21 (Cdkn1A) by PCAF and Set1 recruitment to its promoter for histone H3 acetylation and methylation. We propose a role for NM1 in the transcriptional response to DNA damage response and maintenance of genome stability.Venit et al. demonstrate a role for Nuclear myosin 1 (NM1) in the DNA Damage Response by affecting the expression of the p53 target, p21, through chromatin remodeling. They used embryonic fibroblasts from mouse model, high content phenotypic profiling and cell assays, RNA-Seq and ChIP-Seq and pull-down assays and show that NM1 is required for the recruitment of PCAF and SET1 to the p21 gene in response to etoposide.