Human Ind1, an Iron-Sulfur Cluster Assembly Factor for Respiratory Complex I

Sheftel, Alex D.; Stehling, Oliver; Pierik, Antonio J.; Netz, Daili J. A.; Kerscher, Stefan; Elsässer, Hans–Peter; Wittig, Ilka; Balk, Janneke; Brandt, Ulrich; Lill, Roland

doi:10.1128/mcb.00817-09

Cited by 181 publications

(165 citation statements)

References 81 publications

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“…After the treatment of ETC-1922159, the ZNF502 was found to be downregulated. Its combination with SCO1-WNT10B was confirmed to have lower rank (141) indicating possible direct or indirect combinatorial play in the Wnt pathway during the cancer stages. Similar interpretations could be found for ZNF594 and ZNF740.…”

Section: Dicationmentioning

confidence: 98%

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Revealing ETC-1922159 Affected Unknown 3rd order WNT10B-X-X Combinations, in Silico

Sinha¹

2017

Preprint

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WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stemness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2 nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1 , we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2 nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline's efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3 rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (radial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3 rd order biological hypotheses emerge some of which are confirmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest. KEYWORDS -WNT pathway; porcupine inhibitor ETC-1922159; sensitivity analysis; colorectal cancer; unknown biological hypotheses; combinatorial search space; support vector ranking Conference, from 6-11 August 2017, held Significance WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. Often, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be involved in the pathway. The current work reveals at in silico level, the 3rd order WNT10B associated combinations that might be affected by the admin...

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Section: Dicationmentioning

confidence: 98%

“…NUBPL (or the nucleotide-binding protein-like) encodes the iron-sulfur (Fe/S) protein (IND1) and has a role in the assembly of mitochondrial complex 1 141 . Mitochondrial complex 1 is a member of the mitochondrial respiratory chain.…”

Section: Dicationmentioning

confidence: 99%

Revealing ETC-1922159 Affected Unknown 3rd order WNT10B-X-X Combinations, in Silico

Sinha¹

2017

Preprint

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“…The 14q12 breakpoint is at position g.32,248,943_ 32,248,944dupATAAGATAACAAG, within IVS6 of NUBPL (Fig. 2), a member of the Mrp/NBP35 ATPbinding protein family, and critical for the assembly of human respiratory mitochondrial CI (Sheftel et al 2009). Recently, recessive mutations in NUBPL have been implicated in the genetic etiology of CI deficiency [OMIM #252010], a mitochondrial respiratory chain defect that is caused by mutations in multiple different nuclear, mitochondrial, or X-linked genes (Calvo et al 2010;Fassone and Rahman 2012).…”

Section: Breakpoints and Candidate Genesmentioning

confidence: 99%

“…One of these assembly factors is NUBPL, the depletion of which causes CI deficiency (OMIM #252010) (Tucker et al 2012;Kevelam et al 2013). Incorporation of Fe/S clusters into CI subunits by NUBPL is indispensable for electron transfer activity of CI (Sheftel et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Clinical Severity of PGK1 Deficiency Due To a Novel p.E120K Substitution Is Exacerbated by Co-inheritance of a Subclinical Translocation t(3;14)(q26.33;q12), Disrupting NUBPL Gene

et al. 2015

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Carriers of cytogenetically similar, apparently balanced familial chromosome translocations not always exhibit the putative translocation-associated disease phenotype. Additional genetic defects, such as genomic imbalance at breakpoint regions or elsewhere in the genome, have been reported as the most plausible explanation.By means of comprehensive molecular and functional analyses, additional to careful dissection of the t(3;14) (q26.33;q12) breakpoints, we unveil a novel X-linked PGK1 mutation and examine the contribution of these to the extremely severe clinical phenotype characterized by hemolytic anemia and neuromyopathy.The 3q26.33 breakpoint is 40 kb from the 5 0 region of tetratricopeptide repeat domain 14 gene (TTC14), whereas the 14q12 breakpoint is within IVS6 of nucleotide-binding protein-like gene (NUBPL) that encodes a mitochondrial complex I assembly factor. Disruption of NUBPL in translocation carriers leads to a decrease in the corresponding mRNA accompanied by a decrease in protein level. Exclusion of pathogenic genomic imbalance and reassessment of familial clinical history indicate the existence of an additional causal genetic defect. Consequently, by WES a novel mutation, c.358G>A, p.E120K, in the X-linked phosphoglycerate kinase 1 (PGK1) was identified that segregates with the phenotype. Specific activity, kinetic properties, and thermal stability of this enzyme variant were severely affected. The novel PGK1 mutation is the primary genetic alteration underlying the reported phenotype as the translocation per se only results in a subclinical phenotype. Nevertheless, its co-inheritance presumably exacerbates PGK1-deficient phenotype, most likely due to a synergistic interaction of the affected genes both involved in cell energy supply.

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“…Of these two chaperones, only CIA30 is conserved in mammals and plants. Another chaperone, IND1, is participating in the assembly of Fe-S cofactors and subunits of complex I in yeast Yarrowia lipolytica [15] and is well conserved in human [16] and plants. In the past few years, the discovery of six assembly factors (C20ORF7, C8ORF38, FOXRED1, NDUFAF2, NDUFAF3, and NDUFAF4) provided a significant insight into the assembly process of human complex I (see [17] for a review).…”

Section: Main Components Of the Respiratory Chainmentioning

confidence: 99%

Respiratory-deficient mutants of the unicellular green alga Chlamydomonas: A review

et al. 2014

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Genetic manipulation of the unicellular green alga Chlamydomonas reinhardtii is straightforward. Nuclear genes can be interrupted by insertional mutagenesis or targeted by RNA interference whereas random or site-directed mutagenesis allows the introduction of mutations in the mitochondrial genome. This, combined with a screen that easily allows discriminating respiratorydeficient mutants, makes Chlamydomonas a model system of choice to study mitochondria biology in photosynthetic organisms. Since the first description of Chlamydomonas respiratory-deficient mutants in 1977 by random mutagenesis, many other mutants affected in mitochondrial components have been characterized. These respiratory-deficient mutants increased our knowledge on function and assembly of the respiratory enzyme complexes. More recently some of these mutants allowed the study of mitochondrial gene expression processes poorly understood in Chlamydomonas. In this review, we update the data concerning the respiratory components with a special focus on the assembly factors identified on other organisms. In addition, we make an inventory of different mitochondrial respiratory mutants that are inactivated either on mitochondrial or nuclear genes. Opposed Reviewers:Claire Remacle -Génétique des microorganismes -Institut de Botanique B22 Boulevard du Rectorat, 27 -Université de Liège-B-4000 Liège, Belgique Tel +32 4 3663812 -Fax +32 4 3663840 e-mail: c.remacle@ulg.ac.be First, we wish to thank the two anonymous reviewers for their constructive comments. We found their suggestions very helpful to improve the quality of our manuscript. We have addressed all the points they raised and have modified the text accordingly. A detailed response to reviewers' comments is included below.We believe we have addressed all referees' comments and we hope this revised version is now suitable for publication in Biochimie.We are looking forward to hearing from you, With best regards, Cover LetterResponse to reviewers The text has been modified in order to give more background details on the methodology used to create and screen respiratory mutants in Chlamydomonas. The main modifications correspond to: Paragraph 2.3: -p8. A figure (Fig. 4) has been added in order to provide more information on dark-dier/slow growth screens for different classes of mutant.-p9. The mitochondrial transformation method used in Chlamydomonas has been detailed.Paragraph 2.4: -p10. The TTC-based screen has been explained.Finally, all along the text the methods used to create nuclear and mitochondrial mutants has been indicated. Also, the text could benefit from being proof-read by a native English speaker as the grammar is a little awkward in places. I highlight a couple of points below, but there are a number of other places where the English could be improved for clarity.The text has been proof-read by a good English speaker as requested and the text has been modified according to the comments.Minor points:1. Abstract, line 1: "the genetics" have been replaced by "genetic manipu...

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Human Ind1, an Iron-Sulfur Cluster Assembly Factor for Respiratory Complex I

Cited by 181 publications

References 81 publications

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

Clinical Severity of PGK1 Deficiency Due To a Novel p.E120K Substitution Is Exacerbated by Co-inheritance of a Subclinical Translocation t(3;14)(q26.33;q12), Disrupting NUBPL Gene

Respiratory-deficient mutants of the unicellular green alga Chlamydomonas: A review

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