title: Regulation of HFE expression by poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter.
abstract: Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron overload among Caucasians of northern European descent. Over 85% of all cases with HH are due to mutations in the hemochromatosis protein (HFE) involved in iron metabolism. Although the importance in iron homeostasis is well recognized, the mechanism of sensing and regulating iron absorption by HFE, especially in the absence of iron response element in its gene, is not fully understood. In this report, we have identified an inverted repeat sequence (ATGGTcttACCTA) within 1700bp (-1675/+35) of the HFE promoter capable to form cruciform structure that binds PARP1 and strongly represses HFE promoter. Knockdown of PARP1 increases HFE mRNA and protein. Similarly, hemin or FeCl3 treatments resulted in increase in HFE expression by reducing nuclear PARP1 pool via its apoptosis induced cleavage, leading to upregulation of the iron regulatory hormone hepcidin mRNA. Thus, PARP1 binding to the inverted repeat sequence on the HFE promoter may serve as a novel iron sensing mechanism as increased iron level can trigger PARP1 cleavage and relief of HFE transcriptional repression.
authors.affiliation: Biochemistry Laboratory, Northwest Missouri State University, Maryville, MO 64468.
authors.forename: Christopher
authors.initials: C
authors.lastname: Pelham
authors.affiliation: Biochemistry Laboratory, Northwest Missouri State University, Maryville, MO 64468.
authors.forename: Tamara
authors.initials: T
authors.lastname: Jimenez
authors.affiliation: Biochemistry Laboratory, Northwest Missouri State University, Maryville, MO 64468.
authors.forename: Marianna
authors.initials: M
authors.lastname: Rodova
authors.affiliation: Biochemistry Laboratory, Northwest Missouri State University, Maryville, MO 64468.
authors.forename: Angela
authors.initials: A
authors.lastname: Rudolph
authors.affiliation: Biochemistry Laboratory, Northwest Missouri State University, Maryville, MO 64468.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chipps
authors.affiliation: Biochemistry Laboratory, Northwest Missouri State University, Maryville, MO 64468.
authors.forename: M Rafiq
authors.initials: MR
authors.lastname: Islam
mesh_terms: D015153:Blotting, Western; D002712:Chlorides / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005290:Ferric Compounds / Q000494:pharmacology; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D000071020:Hemochromatosis Protein; D056945:Hep G2 Cells; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D055029:Inverted Repeat Sequences; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009676:Noxae / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D009676:Noxae; D010446:Peptide Fragments; D012333:RNA, Messenger; D008156:Luciferases; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C024555:ferric chloride
keywords: Cruciform; HAMP; HFE; HH; Inverted repeat; Negative element; PARP1; hemochromatosis; hemochromatosis protein; poly(ADP-ribose) polymerase-1