NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer.
NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer.
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NR4A1调节立即早期基因的表达，抑制癌症中的复制应激。
DOI：
10.1016/j.molcel.2021.09.016
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发表时间：
2021-10-07
期刊：
影响因子：
16
通讯作者：
Haber DA
中科院分区：
文献类型：
--
作者：
Guo H;Golczer G;Wittner BS;Langenbucher A;Zachariah M;Dubash TD;Hong X;Comaills V;Burr R;Ebright RY;Horwitz E;Vuille JA;Hajizadeh S;Wiley DF;Reeves BA;Zhang JM;Niederhoffer KL;Lu C;Wesley B;Ho U;Nieman LT;Toner M;Vasudevan S;Zou L;Mostoslavsky R;Maheswaran S;Lawrence MS;Haber DA
癌症中致癌信号的解除会引发复制应激。即时早期基因（Immediate Early Genes，简称IEGs）在应激信号发出后迅速而短暂地表达，有助于机体的综合反应。在这里，我们发现孤儿核受体NR4A1定位于整个基因体和eggs的3 ' -UTR，在那里它抑制RNA Pol II的转录延伸，产生r环和可访问的染色质结构域。急性复制应激导致NR4A1的立即解离和转录平衡的IEG表达的爆发。NR4A1的异位表达增强了乳腺癌细胞的肿瘤发生，而其缺失导致大量染色体不稳定和增殖失败，这是由其IEG靶FOS的表达失调所驱动的。大约一半的乳腺癌和其他原发性癌症在IEG基因体上表现出可接近的染色质结构域，与这种应激调节途径一致。保留这种机制以适应致癌复制应激的癌症可能依赖于NR4A1进行增殖。郭等人通过研究患者源性乳腺癌细胞的肿瘤发生，通过转录加工检查点发现NR4A1是复制应激诱导的直接早期基因表达的主要调控因子。依赖该途径的癌细胞中NR4A1的抑制通过IEG家族成员FOS的不调节表达引发有丝分裂灾难。
Deregulation of oncogenic signals in cancer triggers replication stress. Immediate Early Genes (IEGs) are rapidly and transiently expressed following stressful signals, contributing to an integrated response. Here, we find that the orphan nuclear receptor NR4A1 localizes across the genebody and 3’-UTR of IEGs, where it inhibits transcriptional elongation by RNA Pol II, generating R-loops and accessible chromatin domains. Acute replication stress causes immediate dissociation of NR4A1 and a burst of transcriptionally poised IEG expression. Ectopic expression of NR4A1 enhances tumorigenesis by breast cancer cells, while its deletion leads to massive chromosomal instability and proliferative failure, driven by deregulated expression of its IEG target FOS. Approximately half of breast and other primary cancers exhibit accessible chromatin domains at IEG genebodies, consistent with this stress-regulatory pathway. Cancers that have retained this mechanism in adapting to oncogenic replication stress may be dependent on NR4A1 for their proliferation. Studying tumorigenesis by patient-derived breast cancer cells, Guo et al. identify NR4A1 as a master regulator of replication stress-induced Immediate Early Gene expression, through a transcriptional processing checkpoint. Suppression of NR4A1 in cancer cells dependent on this pathway triggers mitotic catastrophe through unregulated expression of the IEG family member FOS.
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影响因子：
50.3
作者：
Dravis C;Chung CY;Lytle NK;Herrera-Valdez J;Luna G;Trejo CL;Reya T;Wahl GM
通讯作者：
Wahl GM
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
30.8
作者：
Calderon, Diego;Nguyen, Michelle L. T.;Pritchard, Jonathan K.
通讯作者：
Pritchard, Jonathan K.
DOI：
10.1042/bj20141100
发表时间：
2015-04-01
期刊：
The Biochemical journal
影响因子：
--
作者：
通讯作者：
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