DOHH

Last update 08 May 2025

Basic Info

Synonyms

Deoxyhypusine dioxygenase, deoxyhypusine hydroxylase, Deoxyhypusine monooxygenase

+ [5]

Introduction

Catalyzes the hydroxylation of the N(6)-(4-aminobutyl)-L-lysine intermediate produced by deoxyhypusine synthase/DHPS on a critical lysine of the eukaryotic translation initiation factor 5A/eIF-5A. This is the second step of the post-translational modification of that lysine into an unusual amino acid residue named hypusine (PubMed:16371467, PubMed:16533814, PubMed:19706422). Hypusination is unique to mature eIF-5A factor and is essential for its function (By similarity).

100 Clinical Results associated with DOHH

100 Translational Medicine associated with DOHH

0 Patents (Medical) associated with DOHH

102

Literatures (Medical) associated with DOHH

06 Feb 2025·Nature

Aspartate signalling drives lung metastasis via alternative translation

Article

Author: Rossi, Matteo ; Scopelliti, Annalisa ; Liu, Xiao-Zheng ; La Rovere, Rita ; Fendt, Sarah-Maria ; Neven, Patrick ; Altea-Manzano, Patricia ; Maetens, Marion ; Ferreira Campos, Ana Margarida ; Close, Pierre ; Martins Nascentes Melo, Luiza ; Tasdogan, Alpaslan ; Van Baelen, Karen ; Blomme, Arnaud ; Sickmann, Albert ; Doglioni, Ginevra ; El Kharraz, Sarah ; Marine, Jean-Christophe ; Scheele, Colinda L G J ; Tricot, Tine ; Igelmann, Sebastian ; Alkan, H Furkan ; Planque, Mélanie ; Fernández-García, Juan ; Nobis, Max ; Broekaert, Dorien ; Solari, Fiorella A ; Karras, Panagiotis ; Leclercq, Marine ; Vermeire, Ines ; Bultynck, Geert ; Floris, Giuseppe ; Hsieh, Yu-Heng ; Allies, Gabrielle ; Desmedt, Christine ; An, Ning ; Liu, Yawen

Lung metastases occur in up to 54% of patients with metastatic tumours^1,2. Contributing factors to this high frequency include the physical properties of the pulmonary system and a less oxidative environment that may favour the survival of cancer cells³. Moreover, secreted factors from primary tumours alter immune cells and the extracellular matrix of the lung, creating a permissive pre-metastatic environment primed for the arriving cancer cells^4,5. Nutrients are also primed during pre-metastatic niche formation⁶. Yet, whether and how nutrients available in organs in which tumours metastasize confer cancer cells with aggressive traits is mostly undefined. Here we found that pulmonary aspartate triggers a cellular signalling cascade in disseminated cancer cells, resulting in a translational programme that boosts aggressiveness of lung metastases. Specifically, we observe that patients and mice with breast cancer have high concentrations of aspartate in their lung interstitial fluid. This extracellular aspartate activates the ionotropic N-methyl-D-aspartate receptor in cancer cells, which promotes CREB-dependent expression of deoxyhypusine hydroxylase (DOHH). DOHH is essential for hypusination, a post-translational modification that is required for the activity of the non-classical translation initiation factor eIF5A. In turn, a translational programme with TGFβ signalling as a central hub promotes collagen synthesis in lung-disseminated breast cancer cells. We detected key proteins of this mechanism in lung metastases from patients with breast cancer. In summary, we found that aspartate, a classical biosynthesis metabolite, functions in the lung environment as an extracellular signalling molecule to promote aggressiveness of metastases.

01 Dec 2024·Cellular Signalling

CircHIPK3 regulates cementoblast differentiation via the miR-10b-5p/DOHH/NF-κB axis

Article

Author: Mo, Lijuan ; Zhang, Gengming ; Tao, Zhendong ; Zhu, Jiaqi ; Cao, Zhengguo ; Li, Biao ; He, Hong ; Du, Mingyuan

BACKGROUNDIntact cementum is vital for tooth stability and health. Cementoblasts, which line the root surface, are responsible for cementum formation. Recent evidence suggests that circular RNAs (circRNAs) are involved in various cellular functions and may have clinical applications. Although circHIPK3 has been shown to participate in osteogenesis, its role in cementoblast differentiation and mineralization is not well understood.METHODSThe ring structure of circHIPK3 was confirmed using Sanger sequencing and an actinomycin D assay. Subcellular localization of circHIPK3 was assessed using a nucleus-cytoplasm separation assay. RT-qPCR was employed to analyze circHIPK3 expression during cementoblast differentiation and following TNF-α treatment. In vivo, periapical lesions were induced in mouse mandibular first molars to mimic an inflammatory environment, and circHIPK3 expression was evaluated. The interaction of the circHIPK3/miR-10b-5p/DOHH axis was explored through RNA pull-down assays, bioinformatics analysis, and dual-luciferase reporter assays. The effects on cementoblast differentiation and mineralization were assessed by measuring osteogenic markers, alkaline phosphatase (ALP) activity, ALP staining, and alizarin red S staining.RESULTSCircHIPK3 was predominantly located in the cytoplasm of cementoblasts, and its expression was significantly upregulated during cementoblast differentiation. Knockdown of circHIPK3 inhibited cementoblast differentiation and mineralization, whereas its overexpression promoted these processes. Mechanistically, circHIPK3 upregulated DOHH expression by sponging miR-10b-5p, thereby enhancing cementoblast differentiation and mineralization. The NF-κB pathway was found to act downstream of the circHIPK3/miR-10b-5p/DOHH axis in these processes. Additionally, circHIPK3 expression was significantly downregulated in inflammatory environments both in vitro and in vivo. Forced overexpression of circHIPK3 mitigated the inhibitory effects of TNF-α on cementoblast differentiation and mineralization.CONCLUSIONCircHIPK3 acts as a positive regulator of cementoblast differentiation and mineralization through the miR-10b-5p/DOHH/NF-κB axis, playing a crucial role in both normal and pathological cementogenesis.

01 Jun 2024·American Journal of Respiratory and Critical Care Medicine

Hypusine Signaling Promotes Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

Article

Author: Bonnet, Sébastien ; Shimauchi, Tsukasa ; Pelletier, Andréanne ; Provencher, Steeve ; Breuils-Bonnet, Sandra ; Lemay, Sarah-Eve ; Boucherat, Olivier ; Romanet, Charlotte ; Théberge, Charlie ; Grobs, Yann ; Potus, François ; Martineau, Sandra ; Salem, Mabrouka ; Bourgeois, Alice

Rationale: The ubiquitous polyamine spermidine is essential for cell survival and proliferation. One important function of spermidine is to serve as a substrate for hypusination, a posttranslational modification process that occurs exclusively on eukaryotic translation factor 5A (eIF5A) and ensures efficient translation of various gene products. Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive obliteration of the small pulmonary arteries (PAs) caused by excessive proliferation of PA smooth muscle cells (PASMCs) and suppressed apoptosis. Objectives: To characterize the role of hypusine signaling in PAH. Methods: Molecular, genetic, and pharmacological approaches were used both in vitro and in vivo to investigate the role of hypusine signaling in pulmonary vascular remodeling. Measurements and Main Results: Hypusine forming enzymes-deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH)-and hypusinated eukaryotic translation factor 5A are overexpressed in distal PAs and isolated PASMCs from PAH patients and animal models. In vitro, inhibition of DHPS using N¹-guanyl-1,7-diaminoheptane or shRNA resulted in a decrease in PAH-PASMC resistance to apoptosis and proliferation. In vivo, inactivation of one allele of Dhps targeted to smooth muscle cells alleviates PAH in mice, and its pharmacological inhibition significantly decreases pulmonary vascular remodeling and improves hemodynamics and cardiac function in two rat models of established PAH. With mass spectrometry, hypusine signaling is shown to promote the expression of a broad array of proteins involved in oxidative phosphorylation, thus supporting the bioenergetic requirements of cell survival and proliferation. Conclusions: These findings support inhibiting hypusine signaling as a potential treatment for PAH.

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