MEPE/OF45 protects cells from DNA damage induced killing via stabilizing CHK1

Nucleic Acids Res. 2009 Dec;37(22):7447-54. doi: 10.1093/nar/gkp768.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Transformed
  • Checkpoint Kinase 1
  • Cytoprotection
  • DNA Damage*
  • Enzyme Stability
  • Extracellular Matrix Proteins / metabolism
  • Extracellular Matrix Proteins / physiology*
  • Glycoproteins / metabolism
  • Glycoproteins / physiology*
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • Protein Kinases / metabolism*
  • Rats
  • Ubiquitins / metabolism

Substances

  • Extracellular Matrix Proteins
  • Glycoproteins
  • Mepe protein, rat
  • Phosphoproteins
  • Ubiquitins
  • Protein Kinases
  • Checkpoint Kinase 1
  • Chek1 protein, rat