@article {49727,
	title = {Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase.},
	journal = {Nature},
	volume = {477},
	year = {2011},
	month = {2011 Sep 8},
	pages = {225-8},
	abstract = {<p>Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.</p>},
	keywords = {Animals, Bilirubin, Cell Line, Cells, Cultured, Citric Acid Cycle, Computer simulation, Fumarate Hydratase, Fumarates, Genes, Lethal, Genes, Tumor Suppressor, Glutamine, Heme, Heme Oxygenase (Decyclizing), Kidney Neoplasms, Leiomyomatosis, Mice, Mitochondria, Mutation, NAD, Neoplastic Syndromes, Hereditary, Skin Neoplasms, Uterine Neoplasms},
	issn = {1476-4687},
	doi = {10.1038/nature10363},
	author = {Frezza, Christian and Zheng, Liang and Folger, Ori and Rajagopalan, Kartik N and MacKenzie, Elaine D and Jerby, Livnat and Micaroni, Massimo and Chaneton, Barbara and Adam, Julie and Hedley, Ann and Kalna, Gabriela and Tomlinson, Ian P M and Pollard, Patrick J and Watson, Dave G and Deberardinis, Ralph J and Shlomi, Tomer and Ruppin, Eytan and Gottlieb, Eyal}
}
@article {49649,
	title = {Genome-wide analysis reveals novel genes essential for heme homeostasis in Caenorhabditis elegans.},
	journal = {PLoS Genet},
	volume = {6},
	year = {2010},
	month = {2010 Jul},
	pages = {e1001044},
	abstract = {<p>Heme is a cofactor in proteins that function in almost all sub-cellular compartments and in many diverse biological processes. Heme is produced by a conserved biosynthetic pathway that is highly regulated to prevent the accumulation of heme--a cytotoxic, hydrophobic tetrapyrrole. Caenorhabditis elegans and related parasitic nematodes do not synthesize heme, but instead require environmental heme to grow and develop. Heme homeostasis in these auxotrophs is, therefore, regulated in accordance with available dietary heme. We have capitalized on this auxotrophy in C. elegans to study gene expression changes associated with precisely controlled dietary heme concentrations. RNA was isolated from cultures containing 4, 20, or 500 microM heme; derived cDNA probes were hybridized to Affymetrix C. elegans expression arrays. We identified 288 heme-responsive genes (hrgs) that were differentially expressed under these conditions. Of these genes, 42\% had putative homologs in humans, while genomes of medically relevant heme auxotrophs revealed homologs for 12\% in both Trypanosoma and Leishmania and 24\% in parasitic nematodes. Depletion of each of the 288 hrgs by RNA-mediated interference (RNAi) in a transgenic heme-sensor worm strain identified six genes that regulated heme homeostasis. In addition, seven membrane-spanning transporters involved in heme uptake were identified by RNAi knockdown studies using a toxic heme analog. Comparison of genes that were positive in both of the RNAi screens resulted in the identification of three genes in common that were vital for organismal heme homeostasis in C. elegans. Collectively, our results provide a catalog of genes that are essential for metazoan heme homeostasis and demonstrate the power of C. elegans as a genetic animal model to dissect the regulatory circuits which mediate heme trafficking in both vertebrate hosts and their parasites, which depend on environmental heme for survival.</p>},
	keywords = {Animals, Caenorhabditis elegans, Dose-Response Relationship, Drug, Gene Expression Profiling, Gene Expression Regulation, genes, Genome-Wide Association Study, Heme, Homeostasis, HUMANS, Leishmania, Nematoda, Trypanosoma},
	issn = {1553-7404},
	doi = {10.1371/journal.pgen.1001044},
	author = {Severance, Scott and Rajagopal, Abbhirami and Rao, Anita U and Cerqueira, Gustavo C and Mitreva, Makedonka and El-Sayed, Najib M and Krause, Michael and Hamza, Iqbal}
}
