1. Stem Cell Program and Division Hematology/Oncology Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
2. Division of Hematology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Department of Pediatrics, University of Rochester Medical Center, Rochester, New York 14642, USA
4. Department of Pathology, School of Medicine University of Utah, Salt Lake City, Utah 84132, USA
5. Max-Planck-Institut für Entwicklungsbiologie, Spemannstrasse 35, 72076 Tübingen, Germany.
6. Artemis Pharmaceuticals GmbH, 72076 Tübingen, Germany
7. ‡A list of members of the Tübingen 2000 Screen Consortium and their affiliations appears at the end of the paper

Correspondence to: Correspondence and requests for materials should be addressed to L.I.Z. (Email: zon@enders.tch.harvard.edu). The zebrafish grx5, murine grx5, human grx5, zebrafish IRP1 and zebrafish IRP2 sequences are deposited in GenBank under accession numbers DQ083329, DQ083330, DQ083331, DQ083332 and DQ083333, respectively.

Abstract

Iron is required to produce haem and iron–sulphur (Fe–S) clusters, processes thought to occur independently^{1, 2}. Here we show that the hypochromic anaemia in shiraz (sir) zebrafish mutants is caused by deficiency of glutaredoxin 5 (grx5), a gene required in yeast for Fe–S cluster assembly. We found that grx5 was expressed in erythroid cells of zebrafish and mice. Zebrafish grx5 rescued the assembly of grx5 yeast Fe–S, showing that the biochemical function of grx5 is evolutionarily conserved. In contrast to yeast, vertebrates use iron regulatory protein 1 (IRP1) to sense intracellular iron and regulate mRNA stability or the translation of iron metabolism genes^{1, 2}. We found that loss of Fe–S cluster assembly in sir animals activated IRP1 and blocked haem biosynthesis catalysed by aminolaevulinate synthase 2 (ALAS2). Overexpression of ALAS2 RNA without the 5' iron response element that binds IRP1 rescued sir embryos, whereas overexpression of ALAS2 including the iron response element did not. Further, antisense knockdown of IRP1 restored sir embryo haemoglobin synthesis. These findings uncover a connection between haem biosynthesis and Fe–S clusters, indicating that haemoglobin production in the differentiating red cell is regulated through Fe–S cluster assembly.

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