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bioRxiv · 10.1101/2021.06.29.450420

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

Hume, S.·Grou, C. P.·Lascaux, P.·D'Angiolella, V.·Legrand, A. J.·Ramadan, K.·Dianov, G. L.
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Abstract

Efficient entry into S phase of the cell cycle is necessary for embryonic development and tissue homeostasis. 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. TCGA data reveal that this mechanism is hijacked in many cancers, potentially allowing cancer cells to sustain uncontrolled proliferation.

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Hume, S., Grou, C. P., Lascaux, P., D'Angiolella, V., Legrand, A. J., Ramadan, K., Dianov, G. L.. 2021-06-29. The NUCKS1-SKP2-p21/p27 axis controls S phase entry. https://doi.org/10.1101/2021.06.29.450420

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