Sequential Posttranslational Modifications Program FEN1 Degradation during Cell-Cycle Progression
| Autor: | Li Zheng, Zhenxing Wu, Zhigang Guo, Khue Truong, Joonas Jamsen, Changwei Liu, Ying-Jie Wang, Mian Zhou, Yuan Chen, Julie Kanjanapangka, Songbai Liu, Claudia M. Kowolik, Binghui Shen, Na Liu, Tiffany Loh |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
G2 Phase
Proteasome Endopeptidase Complex DNA repair Flap Endonucleases Ubiquitin-activating enzyme Cyclin B SUMO protein Ubiquitin-Activating Enzymes Ubiquitin-conjugating enzyme Genomic Instability Article S Phase Ubiquitin Humans Ubiquitins Molecular Biology biology Cell Cycle G1 Phase Ubiquitination Nuclear Proteins Sumoylation Cell Biology Cell cycle Cell biology DNA Repair Enzymes Biochemistry Ubiquitin-Conjugating Enzymes biology.protein Phosphorylation RNA Splicing Factors Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) Protein Processing Post-Translational Cell Division HeLa Cells |
| Zdroj: | Molecular Cell. 47(3):444-456 |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2012.05.042 |
| Popis: | We propose that cell cycle-dependent timing of FEN1 nuclease activity is essential for cell cycle progression and the maintenance of genome stability. After DNA replication is complete at the exit point of the S-phase, removal of excess FEN1 may be crucial. Here, we report a mechanism that controls the programmed degradation of FEN1 via a sequential cascade of post-translational modifications. We found that FEN1 phosphorylation stimulated its SUMOylation, which, in turn, stimulated its ubiquitination and ultimately led to its degradation via the proteasome pathway. Mutations or inhibitors that blocked the modification at any step in this pathway suppressed FEN1 degradation. Critically, the presence of SUMOylation- or ubiquitination- defective, non-degradable FEN1 mutant protein caused accumulation of Cyclin B, delays in the G1 and G2/M phases and polyploidy. These findings may represent a newly identified regulatory mechanism used by cells to ensure precise cell cycle progression and to prevent transformation. |
| Databáze: | OpenAIRE |
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