Deciphering structure, function and mechanism of lysine acetyltransferase HBO1 in protein acetylation, transcription regulation, DNA replication and its oncogenic properties in cancer

Abstract

HBO1 complexes are major acetyltransferase responsible for histone H4 acetylation in vivo, which belongs to the MYST family. As the core catalytic subunit, HBO1 consists of an N-terminal domain and a C-terminal MYST domain that are in charge of acetyl-CoA binding and acetylation reaction. HBO1 complexes are multimeric and normally consist of two native subunits MEAF6, ING4 or ING5 and two kinds of cofactors as chromatin reader: Jade-1/2/3 and BRPF1/2/3. The choices of subunits to form the HBO1 complexes provide a regulatory switch to potentiate its activity between histone H4 and H3 tails. Thus, HBO1 complexes present multiple functions in histone acetylation, gene transcription, DNA replication, protein ubiquitination, and immune regulation, etc. HBO1 is a co-activator for CDT1 to facilitate chromatin loading of MCM complexes and promotes DNA replication licensing. This process is regulated by mitotic kinases such as CDK1 and PLK1 by phosphorylating HBO1 and modulating its acetyltransferase activity, therefore, connecting histone acetylation to regulations of cell cycle and DNA replication. In addition, both gene amplification and protein overexpression of HBO1 confirmed its oncogenic role in cancers. In this paper, we review the recent advances and discuss our understanding of the multiple functions, activity regulation, and disease relationship of HBO1.

Keywords: BRD1; CDK11; Jade-1; KATs; MOF; ORC1; T cell; YAP1.

Fig. 1

HBO1 is a MYST lysine acetyltransferase. a HBO1 consists of the N-terminal domain (NTD) and MYST domain. b HBO1 comprises a conserved MYST domain in the C-terminus. Cartoon models indicate the highly conserved MYST domain of protein family members MYST1 (also known as MOF or KAT8) (177–449 a.a, PDB: 5WCI), HBO1 (also known as MYST2, or KAT7) (336–606 a.a, PDB: 5GK9), and MYST3 (also known as MOZ, or KAT6A) (497–780 a.a, PDB: 2OZU). BRPF2 (also called BRD1) binds to HBO1 in a cervical-loop structure proximity to the MYST domain to facilitate histone binding. c NTD of HBO1 consists of a number of loops and a small part of the helix. The structure is highly flexible, which may provide abundant conformation changes for HBO1 activity regulation or protein binding

Fig. 2

HBO1 is a multifunctional acetyltransferase. a HBO1 displays the activities of acetyltransferase, propionyltransferase, transcriptional activation or repression and ubiquitin E3 ligase. b HBO1 affords transcriptional activation activity toward SRC-1α/PR, whereas suppresses the activity of NF-κB and AR. c In the assembly of prereplicative complexes in late mitosis, HBO1 binds to CDT1, recognizes and acetylates N-terminal tail of histone H4, and facilitates the loading of MCM complexes to the chromatin. Binding of Geminin to CDT1 or HBO1 inhibits both the licensing activity of CDT1 and acetyltransferase activity of HBO1, which might provide a strategy to inhibit DNA rereplication. d HBO1 is targeted for ubiquitin-mediated degradation by two E3 ubiquitin ligases CRL4 and SCF complexes

Fig. 3

Regulation of HBO1 acetyltransferase activity. a References based protein–protein interaction networks of HBO1 with its cofactors and partner proteins. b HBO1 forms complexes with MEAF6, ING4, ING5 or BRPF1, BRPF2, BRPF3 or Jade-1, Jade-2, Jade-3, for binding to and acetylation histone H3 or H4. JADE1/2/3 directs acetylation toward the H4 tail (K5, K8 and K12), whereas BRPF1/2/3 targets H3 acetylation (K14). c Schematic diagram presented the sequence alignment of HBO1 among species. The vertical lines represent residue variants between the species. HBO1 is a conserved and widely expressed lysine acetyltransferase. However, there is a deletion (from 55 to 110 a.a.) in xenopus, zebrafish or partial tissues of mouse (brain/central nervous system or retina) in the N-terminus of HBO1. Interestingly, this sequence does not match any known motifs but consists of serine/threonine residues in rich abundance that may serve as phosphorylation sites for kinases such as CDKs and PLK1. d Lys432 is a conserved site in the MYST domain shared by MYST protein family located near the binding site of acetyl-CoA. It is autoacetylation and may regulate acetyltransferase activity and protein stability. e A proposed model suggests that NTD provides a regulatory switch for HBO1 activity. HBO1 includes two separate domains, the NTD (N-terminal domain) and MYST domain connecting by a hinge region. The close interaction of NTD with MYST domain rigidifies the full activation of HBO1 complexes, whereas conformation changes induced by modifications such as phosphorylation and acetylation, or binding of cofactor and substrate release MYST domain from the inhibition of NTD and subsequently switch the full activity of HBO1

Fig. 4

The expression of HBO1 and the KATs in normal tissue and cancers. a, b In normal tissue, HBO1 and its cofactors MEAF6, ING4, BRPF2, BRPF3, Jade-1, and Jade-2 are abundant and coincidently expressed in testis, ovary, bone marrow and thyroid. c HBO1 is highly expressed among cancers. d HBO1 gene is generally amplified in cancer genome. e Distribution of mutations in HBO1 from integrative sequencing data. Extended data can be accessed through http://www.cbioportal.org

Fig. 5

Design of targeting molecules and potential strategies for HBO1 inhibition. a MYST domain of HBO1 contains abundant sites for molecule binding. BRPF2-binding site (#1), acetyl-CoA-binding site (#2) and positive charge pocket (#3) provide potential sites for inhibitor binding. b miRNA is another approach for the regulation of HBO1 expression. For example, Hsa-miR-548a-3p is predicted to target on a 7mer-m8 site of 3′ UTR to inhibit HBO1 gene expression