title: The iron-sulfur cluster assembly network component NARFL is a key element in the cellular defense against oxidative stress.
abstract: Aim of this study was to explore cellular changes associated with increased resistance to atmospheric oxygen using high-resolution DNA and RNA profiling combined with functional studies. Two independently selected oxygen-resistant substrains of HeLa cells (capable of proliferating at >80% O2, i.e. hyperoxia) were compared with their parental cells (adapted to growth at 20% O2, but unable to grow at >80% O2). A striking consistent alteration found to be associated with the oxygen-resistant state appeared to be an amplified and overexpressed region on chromosome 16p13.3 harboring 21 genes. The driver gene of this amplification was identified by functional studies as NARFL, which encodes a component of the cytosolic iron-sulfur cluster assembly system. In line with this result we found the cytosolic c-aconitase activity as well as the nuclear protein RTEL1, both Fe-S dependent proteins, to be protected by NARFL overexpression under hyperoxia. In addition, we observed a protective effect of NARFL against hyperoxia-induced loss of sister-chromatid cohesion. NARFL thus appeared to be a key factor in the cellular defense against hyperoxia-induced oxidative stress in human cells. Our findings suggest that new insight into age-related degenerative processes may come from studies that specifically address the involvement of iron-sulfur proteins.
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, 1081BT Amsterdam, The Netherlands. Electronic address: m.corbin@vumc.nl.
authors.forename: Monique V
authors.initials: MV
authors.lastname: Corbin
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, 1081BT Amsterdam, The Netherlands. Electronic address: rockx@vumc.nl.
authors.forename: Davy A P
authors.initials: DA
authors.lastname: Rockx
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, 1081BT Amsterdam, The Netherlands. Electronic address: ab.oostra@vumc.nl.
authors.forename: Anneke B
authors.initials: AB
authors.lastname: Oostra
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, 1081BT Amsterdam, The Netherlands. Electronic address: h.joenje@vumc.nl.
authors.forename: Hans
authors.initials: H
authors.lastname: Joenje
authors.affiliation: Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, 1081BT Amsterdam, The Netherlands. Electronic address: jc.dorsman@vumc.nl.
authors.forename: Josephine C
authors.initials: JC
authors.lastname: Dorsman
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D015153:Blotting, Western; D002470:Cell Survival; D019457:Chromosome Breakage; D003600:Cytosol / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006864:Hydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D054730:Protein Interaction Domains and Motifs; D034741:RNA, Small Interfering / Q000235:genetics; D059467:Transcriptome
chemical_list: C516542:CIAO3 protein, human; D007506:Iron-Sulfur Proteins; D034741:RNA, Small Interfering; D006864:Hydrogenase; C532890:RTEL1 protein, human; D004265:DNA Helicases; D000154:Aconitate Hydratase
keywords: Iron-sulfur proteins; NARFL; Oxygen-resistance; Oxygen-sensitivity; Sister-chromatid cohesion