TY - JOUR

T1 - The NUCKS1-SKP2-p21/p27 axis controls S phase entry

AU - Hume, Samuel

AU - Grou, Claudia P.

AU - Lascaux, Pauline

AU - D’Angiolella, Vincenzo

AU - Legrand, Arnaud J.

AU - Ramadan, Kristijan

AU - Dianov, Grigory L.

N1 - Funding Information: The authors thank Prof. I. Cheeseman (Department of Biology, Massachusetts Institute of Technology), Dr. R. Chapman (Nuffield Department of Medicine, University of Oxford) and Prof. S. Maheswaran (Massachusetts General Hospital Cancer Center, Harvard Medical School) for providing cell lines. We thank Prof. E. O’Neill (Department of Oncology, University of Oxford) for providing plasmids, Prof. A. Østvold (Department of Biochemistry, University of Oslo) for NUCKS1 antibodies, and Dr. S. Mukho-padhyay, Prof. N. Burgess-Brown (Structural Genomics Consortium, University of Oxford), and Dr. S. Khoronenkova (Department of Biochemistry, University of Cambridge) for their help with NUCKS1 purification. The authors thank present and past members of the Dianov and Ramadan labs for discussions and technical help. G.L.D. is supported by grants from the Medical Research Council [H3RWGJ00.H302.1], Cancer Research UK [C5255/A15935], and the Russian Science Foundation grant (№19-74-20069). K.R. is supported by the Medical Research Council Programme (MC_PC-12001/ 1 and MC_UU-00001/1) and Breast Cancer Now (2019DecPR1406). S.H. was supported by the Radcliffe-Oncology Studentship at University College, University of Oxford. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85120042278&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-27124-8

DO - 10.1038/s41467-021-27124-8

M3 - Article

C2 - 34845229

AN - SCOPUS:85120042278

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 6959

ER -