PMID:27037871

Citation	Dik, E, Naamati, A, Asraf, H, Lehming, N and Pines, O (2016) Human Fumarate Hydratase Is Dual Localized by an Alternative Transcription Initiation Mechanism. Traffic 17:720-32
Abstract	Fumarate hydratase (FH, fumarase), is a tricarboxylic acid cycle enzyme localized in the mitochondrial matrix. However, a common theme, conserved from yeast to human, is the existence of a large cytosolic population of FH. FH has been shown to function as a tumor suppressor gene and is now implicated in various diseases. We have previously indicated that the cytosolic echoform of FH has a role in the DNA damage response and specifically in the response to DNA double strand breaks. In fact, recently FH has been shown to be involved in histone demethylation. Therefore, it has become important to understand the underlying mechanism of FH dual subcellular location in human cells. We revealed that in human cells, in contrast to yeast, the FH gene encodes two gene products, one containing and one lacking the mitochondrial targeting sequence. On the basis of expression of endogenous wild-type FH and mutant FH cDNAs from plasmids, RT-PCR, RACE to determine the 5' termini of FH mRNAs, and mass spectrometry of FH products, we show that the mechanism of FH distribution is alternative transcription initiation from a broad promoter. This is contrary to the suggested mechanism for rat liver cells which had claimed alternative translation initiation.
Links	PubMed Online version:10.1111/tra.12397
Keywords	5' Untranslated Regions/genetics; Alternative Splicing/genetics; Amino Acid Sequence; Cell Culture Techniques; Cytosol/enzymology; Fumarate Hydratase/genetics; Fumarate Hydratase/metabolism; HEK293 Cells; HeLa Cells; Humans; Isoenzymes; Mitochondria/enzymology; Mitochondria/genetics; Plasmids; Promoter Regions, Genetic; Protein Biosynthesis; RNA, Messenger/genetics; Transcription Initiation Site; Transcription, Genetic
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:FUMH	part_of	GO:0005737: cytoplasm	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:FUMH	part_of	GO:0005739: mitochondrion	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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