title: ADP ribosylation by PARP-1 suppresses HOXB7 transcriptional activity.
abstract: Interactions with cofactors regulate transcriptional activity and also help HOX proteins to achieve the specificity required for transcriptional regulation of target genes. In this study, we describe a novel protein/protein interaction of HOXB7 with poly (ADP-ribose) polymerase-1 (PARP-1) that involves the homeodomain of HOXB7 and the first zinc finger domain of PARP-1. Upon binding to PARP-1, HOXB7 undergoes poly(ADP-ribosyl)altion resulting in a reduction of its transcriptional activity. Since aspartic acid and glutamic acid residues are acceptors of the ADP ribose moiety transferred by PARP-1, deletion of the evolutionarily conserved C-terminal Glu-rich tail of HOXB7 dramatically attenuates ADP-ribosylation of HOXB7 by PARP-1. Further, a mutant of HOXB7 without the Glu-rich tail loses the ability to be negatively regulated by PARP-1 and becomes transcriptionally more active in luciferase reporter assays. Since the homeodomain is highly conserved among HOX proteins, five other HOX proteins were tested. All six showed interaction with, and were poly(ADP-ribosyl)ated by PARP-1. However, among them, this modification altered the DNA binding activity of only HOXA7 and HOXB7. In summary, this study identifies a new interacting partner of HOX proteins. More importantly, this study reveals a novel mechanism whereby polyADP-ribosylation regulates transcriptional activities of HOX proteins such as HOXB7 and HOXA7.
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. xinyan@jhmi.edu
authors: Xinyan
authors: X
authors: Wu
authors: Stephan
authors: S
authors: Ellmann
authors: Ethel
authors: E
authors: Rubin
authors: Minchan
authors: M
authors: Gil
authors: Kideok
authors: K
authors: Jin
authors: Liangfeng
authors: L
authors: Han
authors: Hexin
authors: H
authors: Chen
authors: Erika M
authors: EM
authors: Kwon
authors: Jianhui
authors: J
authors: Guo
authors: Hyo Chol
authors: HC
authors: Ha
authors: Saraswati
authors: S
authors: Sukumar
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000818:Animals; D055162:Biocatalysis; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D018698:Glutamic Acid; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016335:Zinc Fingers
chemical_list: C115962:HOXA7 protein, human; C490538:HOXB7 protein, human; D018398:Homeodomain Proteins; D000246:Adenosine Diphosphate Ribose; D018698:Glutamic Acid; D004247:DNA; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases