Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, OX3 7DQ, Oxford, UK.
Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
Nat Commun. 2021 Nov 29;12(1):6959. doi: 10.1038/s41467-021-27124-8.
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 SCF 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.
细胞周期的 S 期进入是胚胎发育和组织稳态所必需的。然而，非计划性的 S 期进入会引发 DNA 损伤并促进肿瘤发生，这突出了严格控制的必要性。在这里，我们确定了 NUCKS1-SKP2-p21/p27 轴作为 G1/S 转换的检查点途径。在有丝分裂刺激下，转录因子 NUCKS1 被招募到染色质上，激活 SCF 泛素连接酶的 F 盒组件 SKP2 的表达，导致 p21 和 p27 的降解，并促进进入 S 期。相比之下，DNA 损伤诱导 p53 依赖性 NUCKS1 的转录抑制，导致 SKP2 下调、p21/p27 上调和细胞周期停滞。我们提出，NUCKS1-SKP2-p21/p27 轴整合有丝分裂和 DNA 损伤信号，以控制 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，可能使癌细胞能够持续不受控制地增殖。
