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...

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Bibliographic Details
Published in:Nucleic acids research 2009-12, Vol.37 (22), p.7447-7454
Main Authors: Liu, Shuang, Wang, Hongyan, Wang, Xiang, Lu, Lin, Gao, Ning, Rowe, Peter S.N, Hu, Baocheng, Wang, Ya
Format: Article
Language:English
Subjects:
Animals
Cell Line, Transformed
Checkpoint Kinase 1
Cytoprotection
DNA Damage
Enzyme Stability
Extracellular Matrix Proteins - metabolism
Extracellular Matrix Proteins - physiology
Genome Integrity, Repair and
Glycoproteins - metabolism
Glycoproteins - physiology
Phosphoproteins - metabolism
Phosphoproteins - physiology
Protein Kinases - metabolism
Rats
Ubiquitins - metabolism
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkp768