The NUCKS1-SKP2-p21/p27 axis controls S phase entry

Samuel Hume, Claudia P. Grou, Pauline Lascaux, Vincenzo D’Angiolella, Arnaud J. Legrand (), Kristijan Ramadan () and Grigory L. Dianov ()
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Samuel Hume: University of Oxford
Claudia P. Grou: University of Oxford
Pauline Lascaux: University of Oxford
Vincenzo D’Angiolella: University of Oxford
Arnaud J. Legrand: University of Oxford
Kristijan Ramadan: University of Oxford
Grigory L. Dianov: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-27124-8

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