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Evolutionarily conserved developmental pathways

Chromatin assembly and gene activation: Acetylation, histone escorts, and chromatin assembly factors, and histone deacetylase

Histone acetylation is an evolutionarily conserved process, with conserved biological functions. The cytoplasmic enzyme histone transacetylase B (HAT B) is involved in an evolutionarily conserved acetylation of newly synthesized Histone H4 on lysine 12.

HAT B has been characterized from yeast, and it appears in the cytoplasm as a dimer consisting of two subunits, HAT1p and HAT2p. HAT 1p is the histone transacetylase, while HAT2p is a member of an evolutionarily conserved family of p48 proteins. Members of the p48 family are histone escorts, accompanying newly synthesized histones from cytoplasm to nucleus. The p48 family members are a conserved subfamily of WD-repeat proteins, possessing a motif involved in protein-protein interaction. p48 proteins are found in three contexts: associated with Hat B in the cytoplasm, associated with chromatin assembly factor (CAF-1) in the nucleus, and associated with a histone deacetylase activity. It is likely that cytoplasmic H4 is acetylated by HAT B, carried to the nucleus by CAF-1, where it is assembled into newly synthesized chromatin, and subsequently deacetylated in a process required for chromatin maturation. p48 family members act as histone escorts, accompanying the histones through the process of acetylation, assembly and deacetylation.

Assembly of newly synthesized Histones H3 and H4 is carried out by Chromatin assembly factor 1 (CAF-1). Human CAF-1 is a complex of three polypeptides of apparent molecular masses 150, 60 and 50 kDa. CAF-1 assembles nucleosomes in a replication-dependent manner. The small subunit of CAF-1 (p48) is a member of a highly conserved subfamily of WD-repeat proteins homologous to Drosophila p55, a component of Drosophila CAF-1, and to a subunit of the yeast cytoplasmic histone acetyltransferase B complex component Hat2p.

A second histone transacetylase activity is found in the nucleus. GNC5p, a protein involved in transcriptional activation, is homologous to tetrahymena HAT A, a nuclear histone acetyltransferase. Both the Tetrahymena protein and Gcn5p possess histone acetyltransferase activity and a highly conserved bromodomain. p55 preferentially acetylates histone H3. The presence of a bromodomain known to function in protein-protein interaction in nuclear A-type histone acetyltransferases (but not in cytoplasmic B-type HATs), suggests that HAT A is directed to chromatin through protein interaction to facilitate transcriptional activation. The Drosophila HAT A activity has not been characterized. HAT As, like HAT Bs, are found associated with members of the p48 family of histone escorts. A third activity, histone deacetylase, also associates with p48 family members.

Drosophila                            Homologs in other species ----------                            ----------------------------Histone H4                            Eukaryotes:Histone H4Histone acetyltransferase             Yeast: HATB, HAT1p subunit (see Histone 4)Chromatin assembly factor (CAF-1)     Yeast: HATB, HAT2p subunit (p48 family histone escort)p55 subunit (see H4 and NAP1)         Human: RBAP48Histone H3                            Eukaryotes: Histone H3?                                     Yeast: GCN4p (HATA, catalytic subunit)                                       Tetrahymena p55?                                     Human: Histone deacetylase

date revised: 14 Oct 96

Developmental Pathways conserved in Evolution

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