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Inorganic Pyrophosphatase Is a Component of the Drosophila Nucleosome Remodeling Factor Complex

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Inorganic Pyrophosphatase Is a Component of the Drosophila Nucleosome Remodeling Factor Complex Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Inorganic pyrophosphatase is a component of the Drosophila nucleosome remodeling factor complex David A. Gdula, Raphael Sandaltzopoulos, Toshio Tsukiyama,1 Vincent Ossipow, and Carl Wu2 Laboratory of Molecular Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255 USA The Drosophila nucleosome remodeling factor (NURF) is a protein complex consisting of four polypeptides that facilitates the perturbation of chromatin structure in vitro in an ATP-dependent manner. The 140-kD NURF subunit, imitation switch (ISWI), is related to the SWI2/SNF2 ATPase. Another subunit, NURF-55, is a 55-kD WD repeat protein homologous to the human retinoblastoma-associated protein RbAp48. Here, we report the cloning and characterization of the smallest (38 kD) component of NURF. NURF-38 is strikingly homologous to known inorganic pyrophosphatases. Both recombinant NURF-38 alone and the purified NURF complex are shown to have inorganic pyrophosphatase activity. Inhibition of the pyrophosphatase activity of NURF with sodium fluoride has no significant effect on chromatin remodeling, indicating that these two activities may be biochemically uncoupled. Our results suggest that NURF-38 may serve a structural or regulatory role in the complex. Alternatively, because accumulation of unhydrolyzed pyrophosphate during nucleotide incorporation inhibits polymerization, NURF may also have been adapted to deliver pyrophosphatase to chromatin to assist in replication or transcription by efficient removal of the inhibitory metabolite. [Key Words: Chromatin; ISWI; NURF; pyrophosphatase; remodeling] Received June 15, 1998; revised version accepted August 25, 1998. There is now abundant evidence for a role of chromatin Recent work has led the discovery of several activities structure in the regulation of transcription, and indica- that apparently use the hydrolysis of ATP in the remod- tions that the organization of chromatin can also influ- eling of chromatin templates. The yeast SWI/SNF com- ence other chromosome activities such as recombina- plex facilitates the binding of GAL4 derivatives to tion, replication, and DNA repair. It has been known nucleosomal DNA (Owen-Hughes et al. 1996) and pos- that the wrapping of DNA on the surface of nucleo- sesses the ability to cause a local perturbation of chro- somes, the fundamental units of chromatin structure, matin structure in an ATP-dependent manner (for re- has repressive effects on the transcriptional process (for view, see Henikoff 1993; Carlson and Laurent 1994; Pe- review, see Grunstein 1990; Felsenfeld 1992; Owen- terson and Tamkun 1995; Peterson 1996). The SWI2/ Hughes and Workman 1994; Paranjape et al. 1994; Korn- SNF2 gene itself was identified in genetic screens as berg and Lorch 1995; Pruss et al. 1995; van Holde et al. a positive regulator of a small class of yeast genes, 1995; Fletcher and Hansen 1996; Koshland and Strunni- and encodes a protein homologous to DNA-stimulated kov 1996; Hartzog and Winston 1997; Ramakrishnan ATPases/DNA helicases (Laurent et al. 1993; Cairns et 1997). It is only recently, however, that advances have al. 1994; Coˆte´ et al. 1994). SWI2/SNF2 homologs exist in been made in identifying the underlying mechanisms by both flies (brahma) and humans (BRG1, HBRM) and which nucleosomes are altered to permit the initiation these are also present in large multisubunit protein com- of transcription. Such mechanisms include the intrinsic plexes (Tamkun et al. 1992; Khavari et al. 1993; Mucha- resistance of certain DNAs to curvature, post-transla- rdt and Yaniv 1993; Elfring et al. 1994; Dingwall et al. tional modification of nucleosomal histone proteins, and 1995; Tsukiyama et al. 1995). RSC (remodeling the struc- ATP-dependent remodeling of nucleosome structure (for ture of chromatin) is another yeast protein complex re- review, see Becker 1994; Felsenfeld 1996; Kingston et al. lated to and with similar properties as SWI/SNF (Cairns 1996; Tsukiyama and Wu 1997; Wu 1997). et al. 1996). These complexes are different, however, in that RSC is necessary for cell viability and appears to be 1Present address: Division of Basic Sciences, Fred Hutchinson Cancer more abundant than SWI/SNF. Research Center, Seattle, Washington 98109-1024 USA. Biochemical studies in our laboratory have identified 2 Corresponding author. an ATP-dependent chromatin remodeling complex pres- E-MAIL [email protected]; FAX (301) 435-3697. 3206 GENES & DEVELOPMENT 12:3206–3216 © 1998 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/98 $5.00; www.genesdev.org Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press NURF-38 is an inorganic pyrophosphatase ent in Drosophila embryo extracts, designated the tion, and DNA repair. Although this activity appears to nucleosome remodeling factor (NURF), which facilitates be dispensable for the remodeling of plasmid chromatin a local, transcription factor-mediated perturbation of in vitro, the retention of PPase activity in the NURF chromatin structure within a nucleosomal array (Tsuki- complex suggests that NURF may have a broader func- yama et al. 1994; Tsukiyama and Wu 1995). NURF is tion in the cell nucleus than was indicated previously. composed of four subunits with molecular masses of 215, 140, 55, and 38 kD assembled in a native complex of Results ∼500 kD (Tsukiyama and Wu 1995). The 140-kD subunit has been identified as imitation switch (ISWI), a member The NURF-38 gene encodes a putative inorganic PPase of the SWI2/SNF2 family that is characterized by its NURF 38 is the smallest component among the four ma- highly conserved ATPase domain (Tsukiyama et al. jor polypeptides that copurify at or near stoichiometric 1995). The hydrolysis of ATP during the remodeling of levels with nucleosome remodeling activity (Tsukiyama chromatin is likely to be mediated by ISWI. Unlike the and Wu 1995). We obtained peptide sequences for the SWI/SNF complex, the ATPase activity of NURF is NURF-38 protein by in-gel endopeptidase digestion and stimulated by the presence of nucleosomes rather than Edman degradation sequencing as described previously by free DNA (Tsukiyama and Wu 1995), suggesting that (Tsukiyama and Wu 1995; Martı´nez-Balba´s et al. 1998). NURF recognizes both the protein and DNA compo- The sequences of three peptides were used to design nents of the nucleosome. The interaction between primers for a PCR-based screen of a 0- to 12-hr Dro- NURF and nucleosomes appears to involve the flexible sophila melanogaster embryonic cDNA library. Two histone tails that protrude from the surface of the primer pairs generated a 235-bp and a 711-bp fragment, nucleosome (Georgel et al. 1997). ISWI has been shown respectively; sequencing of the cloned fragments re- recently to be present in at least two other protein com- vealed that the smaller fragment was contained within plexes from Drosophila that affect chromatin structure the larger. in a related but distinct manner—ACF (ATP-utilizing Using the 711-bp fragment as a probe, we obtained two chromatin assembly and remodeling factor; Ito et al. independent genomic clones and four independent 1997) and CHRAC (chromatin accessibility complex; cDNA clones. One of the cDNA clones was presumed to Varga-Weisz et al. 1995, 1997). The presence of ISWI as a contain the entire open reading frame (ORF) based on the common subunit indicates that this ATPase may serve presence of a stop codon in the 5Ј-transcribed, untrans- as the energy-transducing component of chromatin-re- lated region and a poly(A) stretch at the 3Ј terminus. modeling machines. Figure 1A shows the organization of the NURF-38 gene The 55-kD subunit of NURF was found to be identical as deduced from the genomic and cDNA sequences. We to the 55-kD subunit of dCAF-1, a complex that facili- determined that NURF-38 is a single-copy gene that re- tates the assembly of chromatin in vitro (Tyler et al. sides in subdivision 60 C on the right arm of chromo- 1996; Martı´nez-Balba´s et al. 1998). A human counterpart some 2 (data not shown). of NURF-55, RbAp48, was originally identified as a ret- All peptides for which we obtained amino acid se- inoblastoma binding protein in vitro (Qian et al. 1993), quence data were contained within the predicted protein and is present in several distinct complexes that affect sequence (containing 290 residues with a calculated mo- histone metabolism—the human CAF-1 complex (Ver- lecular weight of 32.7 kD), including those not used in rault et al. 1996) and mammalian histone deacetylase primer design (Fig. 1B). A BLAST search (Altschul et al. complexes (Taunton et al. 1996; Hassig et al. 1997; 1990) of existing databases revealed that NURF-38 had Zhang et al. 1997). RbAp46 (a smaller variant of extensive amino acid sequence identity with inorganic RbAp48), was demonstrated to be a subunit of the hu- PPases (Fig. 1B). Overall, this identity can be as high as man Hat1 histone acetyltransferase (HAT) complex, and 53.9%; when the central portion of the PPase sequence is was shown to enhance the ability of the Hat1 complex to examined, the identity increases to ∼70% for yeast, Dro- bind its histone substrates, thereby increasing its activ- sophila, nematode, and mammalian proteins. Most ity (Verreault et al. 1998). The counterparts of NURF-55 striking is the absolute conservation of the 14 amino in yeast, Hat2p and MSI1p, are members of a HAT com- acid residues determined by crystallographic studies to plex (Parthun et al. 1996) and the yeast CAF-1 complex be in the active site of the Saccharomyces cerevisiae (Kaufman et al. 1997), respectively. Overall, the results enzyme (Cooperman et al. 1992 and references therein). suggest that this conserved subfamily of WD repeat pro- These include an invariant arginine (arginine-78 in S. teins may assist targeting of protein complexes to chro- cerevisiae, arginine-81 in D.
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