The nucleosome remodeling factor

Abstract

An essential component of the chromatin remodeling machinery is NURF (Nucleosome Remodeling Factor), the founding member of the ISWI family of chromatin remodeling complexes. In vertebrates and invertebrates alike, NURF has many important functions in chromatin biology including regulating transcription, establishing boundary elements, and promoting higher order chromatin structure. Since NURF is essential to many aspects of chromatin biology, knowledge of its function is required to fully understand how the genome is regulated. This review will summarize what is currently known of its biological functions, conservation in the most prominent model organisms, biochemical functions as a nucleosome remodeling enzyme, and its possible relevance to human cancer.

Fig. 1

Diagram of the NURF remodeling complex and its associated subunits. (A) Cartoon showing the subunit composition of D. melanogaster and H. sapiens NURF complexes. D. melanogaster NURF contains 4 subunits: NURF301, the largest and essential subunit; the ISWI ATPase; NURF55, a WD repeat protein; and NURF38, a pyrophosphatase. H. sapiens NURF has homologs strongly related to 3 of these subunits. BPTF is closely related to NURF301, SNF2L to ISWI, and pRBAP46/48 to NURF55. Interestingly, H. sapiens NURF does not contain a homolog of the NURF38 pyrophosphatase. (B) Domain analysis of D. melanogaster NURF subunits. Domains are color coded (cf. Fig. 2).

Fig. 2

NURF301 homologs are found in many widely studied model organisms. (A) Alignment of NURF301 homologs showing the positions of conserved domains. Color codes for domains are the same as in Fig. 1. Sequences used for analysis; H. sapiens NP_872579.2, M. musculus NP_789820.2, T. rubripes ENSTRUG00000008386, X. tropicalis XP_002942992.1, G. gallus ENSGALP00000005731, D. rerio XP_001920272.1, D. melanogaster NP_728507.1, C. elegans NP_001022117.1, A. thaliana AT5G12400.1. (B) Phylogenetic analysis of NURF301 homologs showing relatedness between species. Comparisons were made using the default settings for the Cobalt alignment program [116].

Fig. 3

Strong sequence conservation at C-terminal PHD fingers and bromodomain of NURF301 homologs. (A) Hydrophobic residues important for H3K4me2/3 binding were identified from Ref. [68] and are designated by black arrows. These residues are highly conserved in all species except A. thaliana, making it quite likely that binding to H3K4me2/3 is conserved in most species. (B) Alignment and comparison of PHD1 and PHD2 domains of D. melanogaster, and C. elegans NURF301 and C-terminal PHD finger of A. thaliana. (C) The C-terminal PHD finger of A. thaliana is significantly different from PHD1 and PHD2 as shown by nearest neighbor analysis using default settings for the Cobalt alignment program [116]. (D) Comparison of bromodomains from NURF301 homologs showing strong sequence conservation through evolution. All alignments were made using default settings for the Clustal W program [117].

Fig. 4

Conserved domains and sequences diagnostic for the NURF301 protein family. (A) Alignment and comparison of N-terminal DDT and PHD fingers from NURF301 homologs showing strong sequence conservation through evolution. (B) Alignment and comparison of conserved sequences near the N-terminal DDT and PHD fingers from NURF301 homologs showing strong sequence conservation through evolution. This region, encompassing the N-terminal DDT domain and PHD finger, is diagnostic of NURF301 homologs. Alignments were made using default settings for the Clustal W program [117].

Fig. 5

ISWI homologs are found in all widely studied model organisms. (A) The domain structure of D. melanogaster ISWI. Because the sequence of D. melanogaster ISWI and its homologs is so highly conserved, a single homolog is presented showing the position of conserved domains. Color codes for domains are the same as in Fig. 1. (B) Phylogenetic analysis of ISWI homologs showing relatedness between species. Species with two ISWI homologs can be segregated into SNF2H and SNF2L variants. Comparisons were made using the default settings for the Cobalt alignment program [116]. Sequences used for analysis; A. thaliana NP_850847.1 and NP_187291.2, S. cerevisiae NP_009804.1 and NP_014948.1, G. gallus XP_420329.2 and XP_001234486.1, D. melanogaster NP_523719.1, C. elegans NP_498468.2, X. tropicalis XP_002931866.1 and NP_001007993.1, T. rubripes ENSTRUP00000036063, H. sapiens NP_003060.2 and NP_003592.2, M. musculus NP_444353.3 and NP_444354.2, D. rerio NP_001075098.1 and NP_001093467.1.