Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27124-8
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Funding
- Medical Research Council [H3RWGJ00.H302.1]
- Cancer Research UK [C5255/A15935]
- Russian Science Foundation [19-74-20069]
- Medical Research Council Programme [MC_PC-12001/1, MC_UU-00001/1]
- Breast Cancer Now [2019DecPR1406]
- Radcliffe-Oncology Studentship at University College, University of Oxford
- Russian Science Foundation [19-74-20069] Funding Source: Russian Science Foundation
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Efficient entry into S phase of the cell cycle is controlled by the NUCKS1-SKP2-p21/p27 axis. This pathway integrates mitogenic and DNA damage signals to regulate cell cycle progression, with potential implications in cancer development.
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. 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.
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