Cell cycle-dependent chromatin shuttling of HBO1–JADE1 histone acetyl transferase (HAT) complex

Abstract

HAT HBO1 interacts with 2 isoforms of JADE1: JADE1S and JADE1L. JADE1 promotes acetylation of nucleosomal histones by HBO1. HBO1–JADE1 complex facilitates cell proliferation by unclear mechanisms. Here we report intracellular chromatin shuttling of HBO1–JADE1 complex during mitosis coupled to phosphorylation of JADE1. In interphase of dividing cells JADE1S was localized to the nucleus and associated with chromatin. As cells approached mitosis, specifically prophase, JADE1S dissociated from chromatin and associated with cytoplasm. JADE1S chromatin re-association began in telophase and paralleled nuclear envelope membrane reassembly. By early G1, JADE1S was re-associated with chromatin and localized to the nucleus. Importantly, cytoplasmic but not chromatin-associated JADE1 protein was phosphorylated. Mass-Spectrometric analysis of JADE1S protein isolated from G2/M-arrested cells identified 6 phosphorylated amino acid residues: S89, T92, S102, S121, S392, and T468, including 3 novel sites. Temporally, JADE1S phosphorylation and dephosphorylation during mitosis correlated with JADE1S chromatin dissociation and recruitment. JADE1S chromatin recruitment was accompanied by the global histone H4 acetylation. Pharmacological inhibitor of Aurora A kinase prevented JADE1S protein band shift and chromatin dissociation, suggesting regulatory function for phosphorylation. In vivo experiments supported our in vitro results. In mouse kidneys, JADE1S transiently accumulated in the cytoplasm of tubular epithelial cells during kidney regeneration. The transient increase in the number of cells with cytoplasmic JADE1S directly correlated with activation of tubular cell proliferation and inversely correlated with the number of cells with nuclear JADE1S staining, supporting biological role of HBO1–JADE1 shuttling during organ regeneration.

The novel function of JADE1S in cytokinesis of epithelial cells

“…The molecular and cellular function of the short isoform of JADE1 is the most described so far by us and others. 4,[6][7][8][9][10][11][12] The JADE1 protein is associated with chromatin and is a candidate transcription factor. 7 JADE1 promotes histone H4 acetylation by associating with a histone H4-specific endogenous HAT in cultured cells and in vitro.…”

Jade-1S phosphorylation induced by CK1α contributes to cell cycle progression

“…20 Of interest, activation of PLK1 prior to mitosis onset is achieved through phosphorylation by Aurora A, 44,45 a kinase previously noted to indirectly lead to Jade-1S phosphorylation. 13 In light of the interphase roles of PLK1, 42 it is particularly interesting that upregulated interactors identified for the mutant Jade-1S S18/20A included TOPORS, which, like the Jade1S interacting partner Kat7/HBO1, is associated with recognition of genotoxic stress 15,46 and regulated by PLK1. 47,48 Given a requirement for PLK1 in cell cycle progression especially after DNA damage, 49,50 and the links between tissue repair and Jade1S described above, a relationship between Jade-1S and PLK1 during the cell cycle is intriguing.…”

“…We previously showed that NPHP4, which localizes to the primary cilium, a post-mitotic structure, stabilises de-phosphorylated nuclear Jade-1S. 17 As Jade-1S does not associate with DNA during mitosis, 13 and our data show that a low-level increase of nuclear Jade-1S influences G1/G0 accumulation, we suggest Jade-1S phosphorylation by CK1a and PLK1 to act as a molecular switch: necessary to remove Jade-1S from the nucleus prior to mitosis and influencing cell cycle exit after. Such a role for Jade-1S has implications for injury repair processes particularly relevant to understanding tubular epithelial repair in kidney disease.…”

“…10 Jade1S was further characterized as a zinc-finger DNA binding protein with histoneacetyltransferase and transcription factor activity 11 and subsequently shown to promote histone H4 acetylation by functioning as a member of the HBO-1 histone acetylation complex. 12 The HBO-1/Jade-1 complex binds DNA in a cell-cycle-dependent manner 13 and is required for H4 acetylation during epithelial cell regeneration 14 as well as during DNA damage response signaling. 15 Jade-1S can furthermore act as an E3-ubiquitin ligase for both nuclear and cytosolic b-catenin to negatively regulate canonical Wnt signaling.…”

Hbo1

“…4 They show in HeLa cells that most HBO1-JADe1 complexes are located in the nucleus and chromatin bound during interphase, whereas, during mitosis, HBO1-JADe1 departs chromatin and the majority of it is cytoplasmic. HBO1-JADe1 returned to chromatin at the end of mitosis at approximately the time of chromosome decondensation and nuclear envelope reformation.…”