Translational autoregulation of thymidylate synthase and dihydrofolate reductase.
The folate-dependent enzymes, thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are critical for providing the requisite nucleotide precursors for maintaining DNA synthesis and DNA repair. In addition to their essential roles in enzyme catalysis, these two enzymes have now been shown to function as RNA binding proteins. Using in vitro and in vivo experimental model systems, we have shown that the functional consequence of binding of TS protein to its own cognate mRNA, as well as binding of DHFR to its own DHFR mRNA, is translational repression. Herein, we review and update studies focusing on the translational autoregulatory control of TS and DHFR expression and discuss the molecular elements that are required for these specific RNA-protein interactions. Moreover, we present evidence showing that abrogation of these normal translational autoregulatory feedback mechanisms provides the molecular basis for the rapid development of cellular drug resistance.
Tai
Ningwen
N
Department of Medicine and Pharmacology, Yale Cancer Center, Yale University School of Medicine and VACT Healthcare System, New Haven, CT 06516, USA.
Schmitz
John C
JC
Liu
Jun
J
Lin
Xiukun
X
Bailly
Michelle
M
Chen
Tian-min
TM
Chu
Edward
E
D000818:Animals; D045744:Cell Line, Tumor; D004260:DNA Repair; D004351:Drug Resistance; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D066298:In Vitro Techniques; D011485:Protein Binding; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism*
D012313:RNA; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase