The NUCKS1-SKP2-p21/p27 axis controls S phase entry.
The NUCKS1-SKP2-p21/p27 axis controls S phase entry.
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DOI：
10.1038/s41467-021-27124-8
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发表时间：
2021-11-29
影响因子：
16.6
通讯作者：
Dianov GL
中科院分区：
文献类型：
--
作者：
Hume S;Grou CP;Lascaux P;D'Angiolella V;Legrand AJ;Ramadan K;Dianov GL
有效进入细胞周期的S期是胚胎发育和组织平衡所必需的。然而，计划外的S期进入会触发DNA损伤并促进肿瘤发生，因此需要严格控制。在这里，我们确定NUCKS1-SKP2-p21/p27轴是G1/S转变的检查点途径。在有丝分裂刺激下，转录因子NUCKS1被招募到染色质上，激活SKP2的表达，SKP2是SCFSKP2泛素连接酶的F-box组分，导致p21和p27的降解，并促进其进入S期。相反，DNA损伤诱导p53依赖性的NUCKS1转录抑制，导致SKP2下调、p21/p27上调和细胞周期阻滞。我们认为NUCKS1-SKP2-p21/p27轴整合了有丝分裂和DNA损伤信号来控制S期进入。癌症基因组图谱（TCGA）数据显示，这种机制在许多癌症中被劫持，可能使癌细胞维持不受控制的增殖。细胞周期进入S期受有丝分裂原的积极调节和DNA损伤的消极调节；然而，如何平衡这些信号是不为人所知的。在这里，作者表明NUCKS1- skp2 - p21/p27轴整合了这些信息，其中NUCKS1转录因子影响p21/p27水平以读取丝裂原：DNA损伤平衡并调节S期进入决策。
Efficient entry into S phase of the cell cycle is necessary for embryonic development and tissue homoeostasis. However, unscheduled S phase entry triggers DNA damage and promotes oncogenesis, underlining the requirement for strict control. Here, we identify the NUCKS1-SKP2-p21/p27 axis as a checkpoint pathway for the G1/S transition. In response to mitogenic stimulation, NUCKS1, a transcription factor, is recruited to chromatin to activate expression of SKP2, the F-box component of the SCFSKP2 ubiquitin ligase, leading to degradation of p21 and p27 and promoting progression into S phase. In contrast, DNA damage induces p53-dependent transcriptional repression of NUCKS1, leading to SKP2 downregulation, p21/p27 upregulation, and cell cycle arrest. We propose that the NUCKS1-SKP2-p21/p27 axis integrates mitogenic and DNA damage signalling to control S phase entry. The Cancer Genome Atlas (TCGA) data reveal that this mechanism is hijacked in many cancers, potentially allowing cancer cells to sustain uncontrolled proliferation. Entry into S phase of the cell cycle is regulated positively by mitogens and negatively by DNA damage; however, how balance of these signals is achieved is not well known. Here the authors show that the NUCKS1-SKP2- p21/p27 axis integrates this information, where the NUCKS1 transcription factor affects levels of p21/p27 to readout the mitogen:DNA damage balance and regulate S phase entry decision.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
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通讯作者：
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作者：
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通讯作者：
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