Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Amino Acid Sequence
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Animals
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Base Sequence
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Binding Sites
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Conserved Sequence
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DNA, Complementary / genetics
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism*
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Humans
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins*
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Mice
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Molecular Sequence Data
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Mutation
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Nervous System Diseases / genetics
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Nervous System Diseases / metabolism
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Repressor Proteins / chemistry
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Sequence Homology, Amino Acid
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Syndrome
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Two-Hybrid System Techniques
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Zinc Fingers / genetics
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Zinc Fingers / physiology*
Substances
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Carrier Proteins
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DNA, Complementary
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Intracellular Signaling Peptides and Proteins
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Nizp1 protein, mouse
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Nuclear Proteins
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Recombinant Fusion Proteins
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Repressor Proteins
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase
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NSD1 protein, human
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Nsd1 protein, mouse