The THAP-zinc finger protein THAP1 associates with coactivator HCF-1 and O-GlcNAc transferase: a link between DYT6 and DYT3 dystonias.
THAP1 is a sequence-specific DNA binding factor that regulates cell proliferation through modulation of target genes such as the cell cycle-specific gene RRM1. Mutations in the THAP1 DNA binding domain, an atypical zinc finger (THAP-zf), have recently been found to cause DYT6 dystonia, a neurological disease characterized by twisting movements and abnormal postures. In this study, we report that THAP1 shares sequence characteristics, in vivo expression patterns and protein partners with THAP3, another THAP-zf protein. Proteomic analyses identified HCF-1, a potent transcriptional coactivator and cell cycle regulator, and O-GlcNAc transferase (OGT), the enzyme that catalyzes the addition of O-GlcNAc, as major cellular partners of THAP3. THAP3 interacts with HCF-1 through a consensus HCF-1-binding motif (HBM), a motif that is also present in THAP1. Accordingly, THAP1 was found to bind HCF-1 in vitro and to associate with HCF-1 and OGT in vivo. THAP1 and THAP3 belong to a large family of HCF-1 binding factors since seven other members of the human THAP-zf protein family were identified, which harbor evolutionary conserved HBMs and bind to HCF-1. Chromatin immunoprecipitation (ChIP) assays and RNA interference experiments showed that endogenous THAP1 mediates the recruitment of HCF-1 to the RRM1 promoter during endothelial cell proliferation and that HCF-1 is essential for transcriptional activation of RRM1. Together, our findings suggest HCF-1 is an important cofactor for THAP1. Interestingly, our results also provide an unexpected link between DYT6 and DYT3 (X-linked dystonia-parkinsonism) dystonias because the gene encoding the THAP1/DYT6 protein partner OGT maps within the DYT3 critical region on Xq13.1.
Mazars
Raoul
R
CNRS, Institut de Pharmacologie et de Biologie Structurale, 205 route de Narbonne, F-31077 Toulouse, France.
Gonzalez-de-Peredo
Anne
A
Cayrol
Corinne
C
Lavigne
Anne-Claire
AC
Vogel
Jodi L
JL
Ortega
Nathalie
N
Lacroix
Chrystelle
C
Gautier
Violette
V
Huet
Gaelle
G
Ray
Aurélie
A
Monsarrat
Bernard
B
Kristie
Thomas M
TM
Girard
Jean-Philippe
JP
D000117:Acetylglucosamine; D020816:Amino Acid Motifs; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D041321:Chromosomes, Human, X / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004421:Dystonia / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells; D040181:Genetic Diseases, X-Linked; D006367:HeLa Cells; D051863:Host Cell Factor C1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D040901:Proteomics; D012262:Ribonucleoside Diphosphate Reductase; D014158:Transcription, Genetic / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics; D016335:Zinc Fingers
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D009687:Nuclear Proteins; C474080:THAP1 protein, human; D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D017351:N-Acetylglucosaminyltransferases; D000117:Acetylglucosamine