TheOncogenePDRG1IsAnInteractionTargetOfMethionine.docx

PAGE  PAGE 45 The Oncogene PDRG1 Is An Interaction Target Of Methionine Adenosyltransferases Claudia Pérez1*, Francisco J. Pérez-Zú?iga1*, Francisco Garrido1, Edel Reytor1, Francisco Portillo1,2,3, María A. Pajares1,2? 1Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain. 2Instituto de Investigación Sanitaria La Paz (IdiPAZ), Paseo de la Castellana 261, 28046 Madrid, Spain. 3Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, 28029 Madrid *These authors contributed equally to this work. ?To whom correspondence should be addressed at: Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain. (Phone: 34-915854414; FAX: 34-915854401; email: mapajares@iib.uam.es) Short title: PDRG1 Binds To Nuclear Methionine Adenosyltransferases Keywords: epigenetic modifications, methionine cycle, methylation, prefoldin-like complex, protein-protein interactions, S-adenosylmethionine. Abstract Methionine adenosyltransferases MAT I and MAT III (encoded by Mat1a) catalyze S-adenosylmethionine synthesis in normal liver. Major hepatic diseases concur with reduced levels of this essential methyl donor, which are primarily due to an expression switch from Mat1a towards Mat2a. Additional changes in the association state and even in subcellular localization of these isoenzymes are also detected. All these alterations result in a reduced content of the moderate (MAT I) and high Vmax (MAT III) isoenzymes, whereas the low Vmax (MAT II) isoenzyme increases and nuclear accumulation of MAT I is observed. These changes derive in a reduced availability of cytoplasmic S-adenosylmethionine, together with an effort to meet its needs in the nucleus of damaged cells, rendering enhanced levels of certain epigenetic modifications. In this context, the putative role of protein-protein interactions in the control of S-adenosylmethionine synthesis has