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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

DOI

10.1038/s41467-021-27124-8

Type

Journal article

Journal

Nat Commun

Publication Date

29/11/2021

Volume

12

Keywords

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