![]() ![]() Intriguingly, instead of binding to Imp4, both histones attached to Imp5, which suggests that they primarily associate with Imp5 when they are not bound to each other. This allowed Pardal and Bowman to work out which proteins the H3 and H4 monomers interact with inside cells. They found that both mutants were still imported into the nucleus, but were not incorporated into chromatin. To overcome this issue, Pardal and Bowman designed H3 and H4 proteins which are unable to dimerize, and transiently expressed these mutant proteins in cells cultured in the laboratory. The nuclear import, dimerization, and incorporation of histone H3 and H4 into chromatin occur very rapidly, making it difficult to track each individual step. Now, in eLife, Alonso Pardal and Andrew Bowman from the University of Warwick – who are part of the research group that conducted the 2018 study – report new findings confirming this theory ( Pardal and Bowman, 2022). ![]() This led the researchers to conclude that H3 and H4 may be transported into the nucleus as individual units or monomers. However, a study in 2018 suggested that preparation of these extracts may have ruptured the nuclear membrane, allowing H3-H4 heterodimers to leak out of the nucleus into the cytosol ( Apta-Smith et al., 2018). This nuclear import model was supported by previous experiments that found H3-H4 heterodimers in samples taken from the cytosol of cells. Freshly made H3 and H4 histones are also incorporated into chromatin throughout a cell’s lifetime during various DNA-related processes, like transcription.įor decades it was assumed that newly synthesized H3 and H4 histones dimerize in the cytoplasm and are then transported into the nucleus by two proteins: importin-4 (Imp4) and the histone chaperone ASF1 ( Grover et al., 2018 Pardal et al., 2019 Bernardes and Chook, 2020). Half of the H3 and H4 histones that go in to the chromatin of each daughter cell are recycled from old tetramers and heterodimers, while the rest are newly synthesized structures. ![]() ![]() In order to divide, cells must replicate their DNA and histone proteins so that the genetic material that will be passed to their daughter cells can be assembled into chromatin. However, it is possible that this H3-H4-ASF1 complex detected in the cytoplasm may have leaked out from the nucleus, meaning the pathway discovered by Pardal and Bowman may be the dominant route H3 and H4 take in to the nucleus. Previously it was thought that H3-H4 heterodimers were formed in the cytoplasm before being imported to the nucleus via a pathway mediated by Imp4 (mauve circle) and ASF1 (pink circle bottom left). The H3-H4 heterodimer is then folded in the nucleus and assembled into one of three complexes which include different chaperone proteins (shown in pink right). Once inside the nucleus, H3 and H4 are transferred to a version of the NASP protein (known as sNASP) and the HAT1–RBBP7 complex, respectively, which together with other proteins help the two monomers dimerize (top middle). ( B) Pardal and Bowman have found a new pathway through which monomers of H3 and H4 are imported from the cytoplasm into the nucleus (black arrow) via the protein Imp5 (yellow circle top left). H3 and H4 also connect in the same way, and the two heterodimers attach to one another via their helices (outlined by the box) to form a tetramer (right). H2A and H2B join together in a head to tail configuration to form a heterodimer (middle). ( A) Three-dimensional structure of the nucleosome, a segment of DNA (grey) wrapped around eight histone proteins: two copies of H3 (green), H4 (orange), H2A (purple) and H2B (pink). ![]()
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