Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage
Abstract The p53 tumor suppressor protein plays a crucial role in detecting and eliminating various oncogenic threats by promoting processes such as cell cycle arrest, DNA repair, senescence, and apoptosis. UBE4B is essential for negatively regulating p53 during normal conditions and following DNA d...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02441-9 |
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| author | Yasser Abuetabh H. Helena Wu Habib Al Yousef Sujata Persad Mary-Pat Schlosser David D. Eisenstat Consolato M. Sergi Roger Leng |
| author_facet | Yasser Abuetabh H. Helena Wu Habib Al Yousef Sujata Persad Mary-Pat Schlosser David D. Eisenstat Consolato M. Sergi Roger Leng |
| author_sort | Yasser Abuetabh |
| collection | DOAJ |
| description | Abstract The p53 tumor suppressor protein plays a crucial role in detecting and eliminating various oncogenic threats by promoting processes such as cell cycle arrest, DNA repair, senescence, and apoptosis. UBE4B is essential for negatively regulating p53 during normal conditions and following DNA damage. In previous studies, we demonstrated that UBE4B targets phosphorylated p53 for degradation in response to DNA damage. However, the regulation of UBE4B in relation to DNA damage in cancer is not well understood. In this study, we show that the UBE4B protein is regulated through a phosphorylation and dephosphorylation mechanism in response to DNA damage. Phosphorylation of UBE4B reduces its binding affinity to p53, leading to an accumulation of p53 in the cell. Wip1 plays a crucial role in the dephosphorylation of UBE4B, which stabilizes the activity of the UBE4B protein in response to DNA damage. UBE4B is primarily phosphorylated through ATR-mediated signaling, which reduces its binding affinity with p53, resulting in the accumulation and activation of p53. When Wip1 is inhibited, there is a significant increase in UBE4B phosphorylation, leading to more p53 accumulation and a reduction in cell growth. Therefore, understanding how UBE4B is regulated in cancer cells in response to DNA-damaging agents could help develop new therapeutic strategies to improve the prognosis for cancer patients. |
| format | Article |
| id | doaj-art-9dd3ad9d4cef4454b67f9c80fbbc8389 |
| institution | DOAJ |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-9dd3ad9d4cef4454b67f9c80fbbc83892025-08-20T03:08:02ZengNature Publishing GroupCell Death Discovery2058-77162025-04-0111111610.1038/s41420-025-02441-9Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damageYasser Abuetabh0H. Helena Wu1Habib Al Yousef2Sujata Persad3Mary-Pat Schlosser4David D. Eisenstat5Consolato M. Sergi6Roger Leng7370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of AlbertaDepartment of Pediatrics, University of Alberta, 11405 - 87 Ave.Department of Pediatrics, University of Alberta, 11405 - 87 Ave.Department of Pediatrics, University of Alberta, 11405 - 87 Ave.Division of Anatomical Pathology, Children’s Hospital of Eastern Ontario (CHEO), University of Ottawa, 401 Smyth Road Ottawa370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of AlbertaAbstract The p53 tumor suppressor protein plays a crucial role in detecting and eliminating various oncogenic threats by promoting processes such as cell cycle arrest, DNA repair, senescence, and apoptosis. UBE4B is essential for negatively regulating p53 during normal conditions and following DNA damage. In previous studies, we demonstrated that UBE4B targets phosphorylated p53 for degradation in response to DNA damage. However, the regulation of UBE4B in relation to DNA damage in cancer is not well understood. In this study, we show that the UBE4B protein is regulated through a phosphorylation and dephosphorylation mechanism in response to DNA damage. Phosphorylation of UBE4B reduces its binding affinity to p53, leading to an accumulation of p53 in the cell. Wip1 plays a crucial role in the dephosphorylation of UBE4B, which stabilizes the activity of the UBE4B protein in response to DNA damage. UBE4B is primarily phosphorylated through ATR-mediated signaling, which reduces its binding affinity with p53, resulting in the accumulation and activation of p53. When Wip1 is inhibited, there is a significant increase in UBE4B phosphorylation, leading to more p53 accumulation and a reduction in cell growth. Therefore, understanding how UBE4B is regulated in cancer cells in response to DNA-damaging agents could help develop new therapeutic strategies to improve the prognosis for cancer patients.https://doi.org/10.1038/s41420-025-02441-9 |
| spellingShingle | Yasser Abuetabh H. Helena Wu Habib Al Yousef Sujata Persad Mary-Pat Schlosser David D. Eisenstat Consolato M. Sergi Roger Leng Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage Cell Death Discovery |
| title | Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage |
| title_full | Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage |
| title_fullStr | Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage |
| title_full_unstemmed | Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage |
| title_short | Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage |
| title_sort | deciphering ube4b phosphorylation dynamics a key mechanism in p53 accumulation and cancer cell response to dna damage |
| url | https://doi.org/10.1038/s41420-025-02441-9 |
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