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Molecular and Cellular Biology, June 2004, p. 5184-5196, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5184-5196.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Nizp1, a Novel Multitype Zinc Finger Protein That Interacts with the NSD1 Histone Lysine Methyltransferase through a Unique C2HR Motif

Anders Lade Nielsen,1 Poul Jørgensen,2 Thierry Lerouge,3 Margarita Cerviño,3 Pierre Chambon,3 and Régine Losson3*

Department of Human Genetics,1 Department of Molecular Biology, Aarhus University, DK-8000 Aarhus C, Denmark,2 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP/Collège de France, F-67404 Illkirch Cedex, France3

Received 15 October 2003/ Returned for modification 21 November 2003/ Accepted 22 March 2004

Haploinsufficiency of the NSD1 gene is a hallmark of Sotos syndrome, and rearrangements of this gene by translocation can cause acute myeloid leukemia. The NSD1 gene product is a SET-domain histone lysine methyltransferase that has previously been shown to interact with nuclear receptors. We describe here a novel NSD1-interacting protein, Nizp1, that contains a SCAN box, a KRAB-A domain, and four consensus C2H2-type zinc fingers preceded by a unique finger derivative, referred to herein as the C2HR motif. The C2HR motif functions to mediate protein-protein interaction with the cysteine-rich (C5HCH) domain of NSD1 in a Zn(II)-dependent fashion, and when tethered to RNA polymerase II promoters, represses transcription in an NSD1-dependent manner. Mutations of the cysteine or histidine residues in the C2HR motif abolish the interaction of Nizp1 with NSD1 and compromise the ability of Nizp1 to repress transcription. Interestingly, converting the C2HR motif into a canonical C2H2 zinc finger has a similar effect. Thus, Nizp1 contains a novel type of zinc finger motif that functions as a docking site for NSD1 and is more than just a degenerate evolutionary remnant of a C2H2 motif.

* Corresponding author. Mailing address: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP/Collège de France, BP 10142, F-67404 Illkirch Cedex, France. Phone: (33) 3 88 65 34 71. Fax: (33) 3 88 65 32 03. E-mail: losson{at}igbmc.u-strasbg.fr.

Molecular and Cellular Biology, June 2004, p. 5184-5196, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5184-5196.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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