MEPE/OF45 protects cells from DNA damage induced killing via stabilizing CHK1.
Matrix extracellular phosphoglycoprotein/osteoblast factor 45 (MEPE/OF45) was cloned in 2000 with functions related to bone metabolism. We identified MEPE/OF45 for the first time as a new co-factor of CHK1 in mammalian cells to protect cells from DNA damage induced killing. We demonstrate here that MEPE/OF45 directly interacts with CHK1. Knocking down MEPE/OF45 decreases CHK1 levels and sensitizes the cells to DNA damage inducers such as ionizing radiation (IR) or camptothicin (CPT)-induced killing. Over-expressing wild-type MEPE/OF45, but not the mutant MEPE/OF45 (depleted the key domain to interact with CHK1) increases CHK1 levels in the cells and increases the resistance of the cells to IR or CPT. MEPE/OF45, interacting with CHK1, increases CHK1 half-life and decreases CHK1 degradation through the ubiquitine-mediated pathway. In addition, the interaction of MEPE/OF45 with CHK1 decreases CHK1 levels in the ubiquitin E3 ligases (Cul1 and Cul4A) complex, which suggests that MEPE/OF45 competes with the ubiquitin E3 ligases binding to CHK1 and thus decreases CHK1 from ubiquitin-mediated proteolysis. These findings reveal an important role of MEPE/OF45 in protecting cells from DNA damage induced killing through stabilizing CHK1, which would provide MEPE/OF45 as a new target for sensitizing tumor cells to radiotherapy or chemotherapy.
Liu
Shuang
S
Beijing Institute of Biotechnology, Beijing 100850, China.
Wang
Hongyan
H
Wang
Xiang
X
Lu
Lin
L
Gao
Ning
N
Rowe
Peter S N
PS
Hu
Baocheng
B
Wang
Ya
Y
D000818:Animals; D002461:Cell Line, Transformed; D000071877:Checkpoint Kinase 1; D019610:Cytoprotection; D004249:DNA Damage; D004795:Enzyme Stability; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D014452:Ubiquitins / Q000378:metabolism
D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C417185:Mepe protein, rat; D010750:Phosphoproteins; D014452:Ubiquitins; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605871:Chek1 protein, rat