Journal Article

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

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

2021

نظرة عامة

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 SCF SKP2 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. Entry into S phase of the cell cycle is regulated positively by mitogens and negatively by DNA damage; however, how balance of these signals is achieved is not well known. Here the authors show that the NUCKS1-SKP2- p21/p27 axis integrates this information, where the NUCKS1 transcription factor affects levels of p21/p27 to readout the mitogen:DNA damage balance and regulate S phase entry decision.

• الناشر: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• موضوع: 13 / 13/106 / 13/109 / 13/31 / 38/70 / 38/71 / 38/89 / 631/1647/2017 / 631/45 / 631/80/474/2073 / 631/80/641/2187 / 631/80/641/2350 / 82/1 / 82/29 / A549 Cells / Animals / Baculoviridae - genetics / Baculoviridae - metabolism / Cancer / Cell cycle / Cell Line, Tumor / Cell Proliferation / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / Chromatin / Cyclin-dependent kinase inhibitor p21 / Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors / Cyclin-Dependent Kinase Inhibitor p21 - genetics / Cyclin-Dependent Kinase Inhibitor p21 - metabolism / Cyclin-Dependent Kinase Inhibitor p27 - antagonists & inhibitors / Cyclin-Dependent Kinase Inhibitor p27 - genetics / Cyclin-Dependent Kinase Inhibitor p27 - metabolism / Damage / Deoxyribonucleic acid / DNA / DNA Damage / Embryogenesis / Embryonic growth stage / Gene Expression Regulation, Neoplastic / Gene silencing / Genomes / HCT116 Cells / HT29 Cells / Humanities and Social Sciences / Humans / Mitogens / multidisciplinary / Nuclear Proteins - antagonists & inhibitors / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Osteoblasts - metabolism / Osteoblasts - pathology / Phosphoproteins - antagonists & inhibitors / Phosphoproteins - genetics / Phosphoproteins - metabolism / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / S phase / S Phase - genetics / S-Phase Kinase-Associated Proteins - antagonists & inhibitors / S-Phase Kinase-Associated Proteins - genetics / S-Phase Kinase-Associated Proteins - metabolism / Science / Science (multidisciplinary) / Sf9 Cells / Signal Transduction / Skp2 protein / Spodoptera / Transcription factors / Tumor Suppressor Protein p53 - deficiency / Tumor Suppressor Protein p53 - genetics / Tumorigenesis / Ubiquitin / Ubiquitin-protein ligase