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

Samuel Hume,Kristijan Ramadan,Claudia P Grou,Pauline Lascaux,Vincenzo D’Angiolella,Arnaud J Legrand,Grigory L Dianov

doi:10.1038/s41467-021-27124-8

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.

Highlights

Efficient entry into S phase of the cell cycle is necessary for embryonic development and tissue homoeostasis
We find that the S phase Kinase-associated Protein 2 (SKP2)-p21/p27 axis acts through NUCKS1 to integrate mitogenic and DNA damage signalling at the G1/S transition
To investigate whether NUCKS1 regulates the transcription of genes involved in cell cycle progression, we cross-compared a list of genes whose expression correlates with NUCKS1 mRNA in tumour samples and cell lines[47], with genes whose promoter NUCKS1 binds in genome-wide ChIP-Seq[16]

Summary

Introduction

Efficient entry into S phase of the cell cycle is necessary for embryonic development and tissue homoeostasis. 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. 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-SKP2p21/p27 axis integrates mitogenic and DNA damage signalling to control S phase entry. 1234567890():,; Entry into S phase of the cell cycle is essential to sustain the proliferation that permits embryonic development and tissue repair[1], but unscheduled S phase entry induces replication stress, DNA damage, and oncogenesis[2,3,4,5]. NUCKS1 depletion inhibits—while its overexpression promotes—xenograft tumour growth[18,39,40], suggesting a direct role in tumourigenesis

Methods

Results

Conclusion