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PLK1 maintains DNA methylation and cell viability by regulating phosphorylation-dependent UHRF1 protein stability. | LitMetric

PLK1 maintains DNA methylation and cell viability by regulating phosphorylation-dependent UHRF1 protein stability.

Cell Death Discov

Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China.

Published: October 2023

AI Article Synopsis

  • PLK1 is a crucial kinase that regulates cell division and, for the first time, has been found to influence DNA methylation, impacting tumor suppressor gene expression.
  • Inhibition of PLK1 disrupts DNA methylation by degrading the UHRF1 protein, which normally stabilizes DNMT1, an enzyme that adds methyl groups to DNA.
  • This study uncovers a new anticancer mechanism of PLK1 inhibitors, suggesting they could promote tumor suppressor gene expression by reducing global DNA methylation.

Article Abstract

PLK1 is a key serine/threonine kinase as well as a master mitotic regulator, but it has never been reported that PLK1 regulates DNA methylation. In the present study, we for the first time found that PLK1 inhibition disrupted global DNA methylation and elevated the expression level of tumor suppressor genes. Mechanistically, we found that PLK1 interacts UHRF1 protein to induce its phosphorylation at serine 265. Phosphorylation is required for the maintenance of UHRF1 protein stability by recruiting a deubiquitinase USP7. Conversely, PLK1 inhibition decreases UHRF1 protein interaction with USP7 and activates the ubiquitin-proteasome pathway, thereby accelerating UHRF1 protein degradation. UHRF1 degradation decreases the recruitment of DNMT1 to chromatin, and decreases the level of genome-wide DNA methylation, thereby elevating the expression of tumor suppressor genes and decreasing cell viability. We here presented the first report on the novel role of PLK1 in DNA methylation maintenance through UHRF1-DNMT1 pathway, and revealed a novel anticancer mechanism of PLK1 inhibitors.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547799PMC
http://dx.doi.org/10.1038/s41420-023-01667-9DOI Listing

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