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

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 checkpoi...

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Published in:	Nature communications Vol. 12; no. 1; pp. 6959 - 14
Main Authors:	Hume, Samuel, Grou, Claudia P., Lascaux, Pauline, D’Angiolella, Vincenzo, Legrand, Arnaud J., Ramadan, Kristijan, Dianov, Grigory L.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 29.11.2021 Nature Publishing Group Nature Portfolio
Subjects:	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
ISSN:	2041-1723, 2041-1723
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-27124-8