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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\n                    <jats:italic>SKP2<\/jats:italic>\n                    , the F-box component of the SCF\n                    <jats:sup>SKP2<\/jats:sup>\n                    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\n                    <jats:italic>NUCKS1<\/jats:italic>\n                    , 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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-021-27124-8","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T06:03:23Z","timestamp":1638165803000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["The NUCKS1-SKP2-p21\/p27 axis controls S phase entry"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4417-0370","authenticated-orcid":false,"given":"Samuel","family":"Hume","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5197-2270","authenticated-orcid":false,"given":"Claudia P.","family":"Grou","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3935-6795","authenticated-orcid":false,"given":"Pauline","family":"Lascaux","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8365-9094","authenticated-orcid":false,"given":"Vincenzo","family":"D\u2019Angiolella","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9429-813X","authenticated-orcid":false,"given":"Arnaud J.","family":"Legrand","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5522-021X","authenticated-orcid":false,"given":"Kristijan","family":"Ramadan","sequence":"additional","affiliation":[]},{"given":"Grigory L.","family":"Dianov","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"27124_CR1","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1111\/j.1469-7580.2008.00931.x","volume":"213","author":"I Neganova","year":"2008","unstructured":"Neganova, I. & Lako, M. 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