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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.

Original publication




Journal article


Nat Commun

Publication Date





A549 Cells, Animals, Baculoviridae, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, DNA Damage, Gene Expression Regulation, Neoplastic, HCT116 Cells, HT29 Cells, Humans, Nuclear Proteins, Osteoblasts, Phosphoproteins, RNA, Small Interfering, Recombinant Proteins, S Phase, S-Phase Kinase-Associated Proteins, Sf9 Cells, Signal Transduction, Spodoptera, Tumor Suppressor Protein p53