Universität zu Köln

Halwas, Kai, Doering, Lennard-Maximilian, Oehlert, Franziska Valentina and Dohmen, R. Juergen (2022). Hypusinated eIF5A Promotes Ribosomal Frameshifting during Decoding of ODC Antizyme mRNA in Saccharomyces cerevisiae. Int. J. Mol. Sci., 23 (21). BASEL: MDPI. ISSN 1422-0067

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Abstract

Polyamines are essential biogenic poly-cations with important roles in many cellular processes and diseases such as cancer. A rate-limiting step early in the biosynthesis of polyamines is the conversion of ornithine to putrescine by the homodimeric enzyme ornithine decarboxylase (ODC). In a conserved mechanism of posttranslational regulation, ODC antizyme (OAZ) binds to ODC monomers promoting their ubiquitin-independent degradation by the proteasome. Decoding of OAZ mRNA is unusual in that it involves polyamine-regulated bypassing of an internal translation termination (STOP) codon by a ribosomal frameshift (RFS) event. Using Saccharomyces cerevisiae, we earlier showed that high polyamine concentrations lead to increased efficiency of OAZ1 mRNA translation by binding to nascent Oaz1 polypeptide. The binding of polyamines prevents stalling of the ribosomes on OAZ1 mRNA caused by nascent Oaz1 polypeptide thereby promoting synthesis of full-length Oaz1. Polyamine depletion, however, also inhibits RFS during the decoding of constructs bearing the OAZ1 shift site lacking sequences encoding the Oaz1 parts implicated in polyamine binding. Polyamine depletion is known to impair hypusine modification of translation factor eIF5A. Using a novel set of conditional mutants impaired in the function of eIF5A/Hyp2 or its hypusination, we show here that hypusinated eIF5A is required for efficient translation across the OAZ1 RFS site. These findings identify eIF5A as a part of Oaz1 regulation, and thereby of polyamine synthesis. Additional experiments with DFMO, however, show that depletion of polyamines inhibits translation across the OAZ1 RFS site not only by reducing Hyp2 hypusination, but in addition, and even earlier, by affecting RFS more directly.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Halwas, Kai UNSPECIFIED UNSPECIFIED UNSPECIFIED Doering, Lennard-Maximilian UNSPECIFIED UNSPECIFIED UNSPECIFIED Oehlert, Franziska Valentina UNSPECIFIED UNSPECIFIED UNSPECIFIED Dohmen, R. Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-665103
DOI:	10.3390/ijms232112972
Journal or Publication Title:	Int. J. Mol. Sci.
Volume:	23
Number:	21
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1422-0067
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INITIATION-FACTOR 5A; MAMMALIAN ORNITHINE-DECARBOXYLASE; DEOXYHYPUSINE SYNTHASE; CLONING VECTORS; CELL VIABILITY; PROTEIN EIF5A; HOST STRAINS; AMINO-ACID; TRANSLATION; YEAST Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66510