Histone chaperones in nucleosome assembly and human disease

Abstract

Nucleosome assembly following DNA replication, DNA repair and gene transcription is critical for the maintenance of genome stability and epigenetic information. Nucleosomes are assembled by replication-coupled or replication-independent pathways with the aid of histone chaperone proteins. How these different nucleosome assembly pathways are regulated remains relatively unclear. Recent studies have provided insight into the mechanisms and the roles of histone chaperones in regulating nucleosome assembly. Alterations or mutations in factors involved in nucleosome assembly have also been implicated in cancer and other human diseases. This review highlights the recent progress and outlines future challenges in the field.

Figure 1. Histone chaperones are key regulators of replication-coupled and replication-independent nucleosome assembly

(a) Histone chaperones coordinate to regulate DNA replication-coupled nucleosome assembly. Once newly synthesized histone H3–H4 is imported into the nucleus, new H3–H4 of the Asf1-H3–H4 complex is transferred to CAF-1 and Rtt106 for (H3–H4)₂ formation and deposition onto newly synthesized DNA. Deposition onto replicated DNA depends, in part, on the interaction between CAF-1 and PCNA. Parental histones are also a source of histones for nucleosome assembly following DNA replication. However, the mechanistic insight is relatively unclear. (b) HIRA and Daxx mediate replication-independent nucleosome assembly of H3.3–H4. In human cells, H3.3–H4 of the Asf1a-H3.3–H4 complex is transferred to HIRA for deposition of H3.3–H4 at genic regions, possibly through interactions with RNA polymerase II and dsDNA. Daxx facilitates deposition of H3.3–H4 at telomere regions, although mechanisms by which Daxx-mediated histone deposition is regulated are currently unclear.

Figure 2. H3–H4 histone chaperones bind a H3–H4 dimer or a (H3–H4)₂ tetramer

(a) Structure of a (H3–H4)₂ tetramer. The structure is from the structure of budding yeast nucleosome core particle (PDB access code: 1ID3). (b) Asf1 interacts with the H3 interface involved in H3–H4 tetramerization and forms the Asf1-H3–H4 heterotrimeric complex (PDB access code: 2HUE). (c) HJURP binds a CENPA-H4 dimer, in part, through interactions with the CENPA interface involved in formation of CENPA-H4 tetramers (PDB access code: 3R45).(d) A model for Rtt106 binding to a (H3–H4)₂ tetramer (Top) Rtt106 contains two domains involved in histone binding: a dimerization domain (DD, PDB access code: 2LHO) and tandem PH domains (PH-PH, PDB access code: 3FSS). (Bottom) Model of the Rtt106 homodimer binding to a (H3–H4)₂ tetramer. Model is constructed using domain structures of Rtt106 (residues 1–301) and atomic coordinates of (H3–H4)₂ from the yeast core nucleosome particle. (e) Deposition of one new (H3–H4)₂ tetramer by Rtt106 effectively inhibits formation of mixed nucleosomes containing one parental and one new H3–H4 dimer.