title: hHR23A is required to control the basal turnover of Chk1.
abstract: Among other functions, the Chk1 protein plays an essential role in coordinating the cellular stress response by determining cell cycle arrest. The levels of Chk1 expression and activity are critical for its functions, especially in cell cycle progression, genomic integrity, cell viability and tissue development. Chk1 protein expression should therefore be tightly controlled both during normal growth and under stress situations. However, it is still unknown how Chk1 protein levels are regulated during normal cell cycle progression. In this study, we show that the effect of hHR23A on Chk1 protein turnover could impact the cell cycle progression observed in hHR23A-knockdown cells. Our results reveal that hHR23A associates with Chk1 through its UBA domains, and that knockdown of hHR23A increases and stabilizes the protein level of Chk1 and its phosphorylation at S347. Knockdown of hHR23A results in proliferation defects and S-phase accumulation. DNA damage reduces the interaction between Chk1 and hHR23A, releasing Chk1 from hHR23A and enhancing S-phase accumulation. Based on these novel findings, we propose that hHR23A acts as a carrier to promote Chk1 degradation through the Ubiquitin Proteasome System. These results strengthen the model in which DNA damage induces Chk1 phosphorylation on chromatin followed by releasing phospho-Chk1 from the chromatin into soluble nucleus and the cytoplasm where Chk1 activates the cell cycle checkpoints; and finally, Chk1 is degraded and checkpoint signaling is terminated.
authors: Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
authors: Xiaotong
authors: X
authors: Tan
authors: Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
authors: Ruei-Yue
authors: RY
authors: Liang
authors: Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan; Department of Nursing, Asia University, Taichung 41354, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan. Electronic address: smchuang@dragon.nchu.edu.tw.
authors: Show-Mei
authors: SM
authors: Chuang
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D010766:Phosphorylation / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016196:S Phase / Q000235:genetics; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; C086985:RAD23A protein, human; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D045643:DNA Repair Enzymes
keywords: Cell cycle; Chk1; hHR23A