title: Sequential posttranslational modifications program FEN1 degradation during cell-cycle progression.
abstract: 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 posttranslational 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, nondegradable 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.
authors: Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing 210046, China.
authors: Zhigang
authors: Z
authors: Guo
authors: Julie
authors: J
authors: Kanjanapangka
authors: Na
authors: N
authors: Liu
authors: Songbai
authors: S
authors: Liu
authors: Changwei
authors: C
authors: Liu
authors: Zhenxing
authors: Z
authors: Wu
authors: Yingjie
authors: Y
authors: Wang
authors: Tiffany
authors: T
authors: Loh
authors: Claudia
authors: C
authors: Kowolik
authors: Joonas
authors: J
authors: Jamsen
authors: Mian
authors: M
authors: Zhou
authors: Khue
authors: K
authors: Truong
authors: Yuan
authors: Y
authors: Chen
authors: Li
authors: L
authors: Zheng
authors: Binghui
authors: B
authors: Shen
mesh_terms: D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D045643:DNA Repair Enzymes / Q000378:metabolism; D045585:Flap Endonucleases / Q000235:genetics* / Q000378:metabolism*; D016193:G1 Phase / Q000502:physiology; D016195:G2 Phase / Q000502:physiology; D042822:Genomic Instability / Q000502:physiology*; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D000072260:RNA Splicing Factors; D016196:S Phase / Q000502:physiology; D058207:Sumoylation / Q000502:physiology; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D000072260:RNA Splicing Factors; C492189:SUMO3 protein, human; C471538:UBA1 protein, human; D014452:Ubiquitins; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D044763:Ubiquitin-Conjugating Enzymes; D045585:Flap Endonucleases; C468317:FEN1 protein, human; D046988:Proteasome Endopeptidase Complex; D044764:Ubiquitin-Activating Enzymes; D045643:DNA Repair Enzymes; C417041:PRPF19 protein, human