Histone chaperones link histone nuclear import and chromatin assembly

Abstract

Histone chaperones are proteins that shield histones from nonspecific interactions until they are assembled into chromatin. After their synthesis in the cytoplasm, histones are bound by different histone chaperones, subjected to a series of posttranslational modifications and imported into the nucleus. These evolutionarily conserved modifications, including acetylation and methylation, can occur in the cytoplasm, but their role in regulating import is not well understood. As part of histone import complexes, histone chaperones may serve to protect the histones during transport, or they may be using histones to promote their own nuclear localization. In addition, there is evidence that histone chaperones can play an active role in the import of histones. Histone chaperones have also been shown to regulate the localization of important chromatin modifying enzymes. This review is focused on the role histone chaperones play in the early biogenesis of histones, the distinct cytoplasmic subcomplexes in which histone chaperones have been found in both yeast and mammalian cells and the importins/karyopherins and nuclear localization signals that mediate the nuclear import of histones. We also address the role that histone chaperone localization plays in human disease. This article is part of a Special Issue entitled: Histone chaperones and chromatin assembly.

Figure 1

Cytoplasmic complexes of H1 and H3-H4 and their import pathways. Histones, importins and interacting proteins are labeled. The star represents Ran-GTP which promotes dissociation of the import complexes. The rings represent nuclear pore complexes in the nuclear membrane, separating the cytoplasm (upper) from the nucleus (lower). NASP refers to both sNASP and tNASP. A. H1 was found in a complex with NASP and a heat shock protein in the cytoplasm of murine cells. NASP promotes import of H1. Question mark denotes unknown import pathway. B. H3.1 containing subcomplexes detected in human cytosol. The proposed order of complex formation is indicated with dashed arrows based on references (45) and (73). Once inside the nucleus, ASF1B can donate H3.1-H4 for chromatin assembly by the CAF1 complex or other assembly proteins. C. Data from yeast and human cells indicates that H3 interacts with the proteins shown, suggesting the possibility of one large import complex. (Question mark indicates that heat shock proteins were found in human cells but not in yeast).

Figure 2

Import of H2A-H2B, Htz1-H2B, Chz1 and Nap1. The exportin Crm1 and the remodeling complex SWR1 are labeled, and the import Kaps are labeled by their numbers (Kap114, Kap123, Kap95 and Kap60) in the model. The histones and chaperones are labeled in the legend (top). The star represents Ran-GTP which either promotes association of the export complex, Crm1-Nap1, or the dissociation of the import complexes, Kap95-Kap60-Chz1 and Kap123-Htz1-H2B. The question marks represent dissociation of Kap114-Nap1-H2A-H2B or Kap114-Nap1-Htz1-H2B complexes, which is facilitated by additional factors. The rings represent nuclear pore complexes in the nuclear membrane, separating the cytoplasm (upper) from the nucleus (lower). A, B. Once inside the nucleus, the chaperones Chz1 or Nap1 can donate Htz1-H2B to the SWR1 complex which incorporates it into chromatin through exchange with H2A-H2B. C. After import, Nap1 is thought to be capable of depositing H2A-H2B dimers in chromatin. Nap1 export is mediated by Crm1, promoting cycles of histone import by Nap1.