A novel function of methionyl-tRNA synthetase in cyclin-dependent kinase 4 mediated cell cycle progression

Abstract

Methionyl-tRNA synthetase (MRS) is one of aminoacyl-tRNA synthetases (ARSs) which charge amino acids to cognate transfer RNAs (tRNAs) in translation. High expression of MRS in various cancers and its nuclear localization during cell proliferation has been reported. With this background information about MRS related to cancer, the present study was attempted to clarify the role of MRS on cell proliferation and cell cycle progression and further to reveal the signal pathway where MRS is involved. A novel role of MRS for triggering cell cycle progression via the stabilization of cyclin-dependent kinase 4 (CDK4), one of cell cycle regulating factors, was shown. The protein level of CDK4 significantly decreased by MRS knock-down or activity inhibition. The protein levels of other cell cycle regulators such as CDK1, CDK2 and CDK6, however, were not affected. The deprivation of methionine or the treatment of methionine analogue reduced the binding of MRS to CDK4 and impeded the cell cycle progression without translation inhibition. It implied that the cell cycle regulating function of MRS was mediated by the interaction between MRS and CDK4 and the catalytic domain of MRS was in charge of the association. This study explains the mechanism of the increased stability of CDK4 in cancer and suggests a novel function of MRS required for the cancer cell proliferation.