Last update 19 Sep 2024

ALKBH3

Last update 19 Sep 2024

Basic Info

Synonyms

ABH3, alkB homolog 3, alpha-ketoglutarate dependent dioxygenase, ALKBH3

+ [6]

Introduction

Dioxygenase that mediates demethylation of DNA and RNA containing 1-methyladenosine (m1A) (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:26863196, PubMed:26863410). Repairs alkylated DNA containing 1-methyladenosine (m1A) and 3-methylcytosine (m3C) by oxidative demethylation (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:25944111). Has a strong preference for single-stranded DNA (PubMed:12486230, PubMed:12594517, PubMed:16174769, PubMed:20714506). Able to process alkylated m3C within double-stranded regions via its interaction with ASCC3, which promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3 (PubMed:22055184). Can repair exocyclic 3,N4-ethenocytosine adducs in single-stranded DNA (PubMed:25797601). Also acts on RNA (PubMed:12594517, PubMed:16174769, PubMed:26863196, PubMed:26863410, PubMed:16858410). Demethylates N(1)-methyladenosine (m1A) RNA, an epigenetic internal modification of messenger RNAs (mRNAs) highly enriched within 5'-untranslated regions (UTRs) and in the vicinity of start codons (PubMed:26863196, PubMed:26863410). Requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:22055184, PubMed:16858410).

Drugs associated with ALKBH3

ALKBH3(HOIST)

Target

ALKBH3

Mechanism

ALKBH3 inhibitors

Active Org.

Hoist KK

Originator Org.-

Active Indication

Pancreatic Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ALKBH3

100 Translational Medicine associated with ALKBH3

0 Patents (Medical) associated with ALKBH3

130

Literatures (Medical) associated with ALKBH3

01 Aug 2024·Journal of Biological Chemistry

Lack of mismatch repair enhances resistance to methylating agents for cells deficient in oxidative demethylation

Article

Author: Lee, Dong-Hyun ; O'Connor, Timothy R ; Itoh, Shunsuke ; Lai, Seigmund Wai Tsuen ; Chen, Shiuan ; Sun, Kelani ; Gutierrez, Roberto ; Battad, Alana ; Shuck, Sarah C ; Chan, Annie Yin S

The human alkylation B (AlkB) homologs, ALKBH2 and ALKBH3, respond to methylation damage to maintain genomic integrity and cellular viability. Both ALKBH2 and ALKBH3 are direct reversal repair enzymes that remove 1-methyladenine (1meA) and 3-methylcytosine (3meC) lesions commonly generated by alkylating chemotherapeutic agents. Thus, the existence of deficiencies in ALKBH proteins can be exploited in synergy with chemotherapy. In this study, we investigated possible interactions between ALKBH2 and ALKBH3 with other proteins that could alter damage response and discovered an interaction with the mismatch repair (MMR) system. To test whether the lack of active MMR impacts ALKBH2 and/or ALKBH3 response to methylating agents, we generated cells deficient in ALKBH2, ALKBH3, or both in addition to Mlh homolog 1 (MLH1), another MMR protein. We found that MLH1^koALKBH3^ko cells showed enhanced resistance toward S_N1- and S_N2-type methylating agents, whereas MLH1^koALKBH2^ko cells were only resistant to S_N1-type methylating agents. Concomitant loss of ALKBH2 and ALKBH3 (ALKBH2^ko3^ko) rendered cells sensitive to S_N1- and S_N2-agents, but the additional loss of MLH1 enhanced resistance to both types of damage. We also showed that ALKBH2^ko3^ko cells have an ATR-dependent arrest at the G₂/M checkpoint, increased apoptotic signaling, and replication fork stress in response to methylation. However, these responses were not observed with the loss of functional MLH1 in MLH1^koALKBH2^ko3^ko cells. Finally, in MLH1^koALKBH2^ko3^ko cells, we observed elevated mutant frequency in untreated and temozolomide treated cells. These results suggest that obtaining a more accurate prognosis of chemotherapeutic outcome requires information on the functionality of ALKBH2, ALKBH3, and MLH1.

21 Jun 2024·Angewandte Chemie International Edition

Small Molecule‐Inducible and Photoactivatable Cellular RNA N1‐Methyladenosine Editing

Article

Author: Niu, Hongxin ; Wang, Hongsheng ; Li, Jiexin ; Xiong, Xiaofeng ; Zhou, Jiawang ; Li, Zigang ; Yang, Xianyuan ; He, Jiaxin ; Asadikaram, Gholamreza ; Lu, Yunqing ; Li, Jian ; Xie, Guoyou ; Yi, Cheng

AbstractN1‐methyladenosine (m1A) modification is one of the most prevalent epigenetic modifications on RNA. Given the vital role of m1A modification in RNA processing such as splicing, stability and translation, developing a precise and controllable m1A editing tool is pivotal for in‐depth investigating the biological functions of m1A. In this study, we developed an abscisic acid (ABA)‐inducible and reversible m1A demethylation tool (termed AI‐dm1A), which targets specific transcripts by combining the chemical proximity‐induction techniques with the CRISPR/dCas13b system and ALKBH3. We successfully employed AI‐dm1A to selectively demethylate the m1A modifications at A8422 of MALAT1 RNA, and this demethylation process could be reversed by removing ABA. Furthermore, we validated its demethylation function on various types of cellular RNAs including mRNA, rRNA and lncRNA. Additionally, we used AI‐dm1A to specifically demethylate m1A on ATP5D mRNA, which promoted ATP5D expression and enhanced the glycolysis activity of tumor cells. Conversely, by replacing the demethylase ALKBH3 with methyltransferase TRMT61A, we also developed a controllable m1A methylation tool, namely AI‐m1A. Finally, we caged ABA by 4,5‐dimethoxy‐2‐nitrobenzyl (DMNB) to achieve light‐inducible m1A methylation or demethylation on specific transcripts. Collectively, our m1A editing tool enables us to flexibly study how m1A modifications on specific transcript influence biological functions and phenotypes.

01 Jun 2024·Journal of Biological Chemistry

ASCC1 structures and bioinformatics reveal a novel helix-clasp-helix RNA-binding motif linked to a two-histidine phosphodiesterase

Article

Author: Syed, Aleem ; Katsonis, Panagiotis ; Thapar, Roopa ; Rosenberg, Daniel J ; Sarker, Altaf H ; Mosammaparast, Nima ; Asthana, Abhishek ; Silverman, Robert H ; Paul, Tanmoy ; Tsai, Miaw-Sheue ; Soll, Jennifer M ; Tainer, John A ; Lichtarge, Olivier ; Tsutakawa, Susan E ; Chinnam, Naga Babu ; Ivanov, Ivaylo ; Bacolla, Albino ; Hammel, Michal ; Arvai, Andrew S

Activating signal co-integrator complex 1 (ASCC1) acts with ASCC-ALKBH3 complex in alkylation damage responses. ASCC1 uniquely combines two evolutionarily ancient domains: nucleotide-binding K-Homology (KH) (associated with regulating splicing, transcriptional, and translation) and two-histidine phosphodiesterase (PDE; associated with hydrolysis of cyclic nucleotide phosphate bonds). Germline mutations link loss of ASCC1 function to spinal muscular atrophy with congenital bone fractures 2 (SMABF2). Herein analysis of The Cancer Genome Atlas (TCGA) suggests ASCC1 RNA overexpression in certain tumors correlates with poor survival, Signatures 29 and 3 mutations, and genetic instability markers. We determined crystal structures of Alvinella pompejana (Ap) ASCC1 and Human (Hs) PDE domain revealing high-resolution details and features conserved over 500 million years of evolution. Extending our understanding of the KH domain Gly-X-X-Gly sequence motif, we define a novel structural Helix-Clasp-Helix (HCH) nucleotide binding motif and show ASCC1 sequence-specific binding to CGCG-containing RNA. The V-shaped PDE nucleotide binding channel has two His-Φ-Ser/Thr-Φ (HXT) motifs (Φ being hydrophobic) positioned to initiate cyclic phosphate bond hydrolysis. A conserved atypical active-site histidine torsion angle implies a novel PDE substrate. Flexible active site loop and arginine-rich domain linker appear regulatory. Small-angle X-ray scattering (SAXS) revealed aligned KH-PDE RNA binding sites with limited flexibility in solution. Quantitative evolutionary bioinformatic analyses of disease and cancer-associated mutations support implied functional roles for RNA binding, phosphodiesterase activity, and regulation. Collective results inform ASCC1's roles in transactivation and alkylation damage responses, its targeting by structure-based inhibitors, and how ASCC1 mutations may impact inherited disease and cancer.

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ALKBH3

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