Structural insights into the interactions and epigenetic functions of human nucleic acid repair protein ALKBH6

Ma, Lulu; Lu, Hongyun; Tian, Zizi; Yang, Meng; Ma, Jun; Shang, Guo Liang; Liu, Yunlong; Xie, Mengjia; Wang, Guoguo; Wu, Wei; Zhang, Ziding; Dai, Shaodong; Chen, Zhongzhou

doi:10.1016/j.jbc.2022.101671

Cited by 14 publications

(7 citation statements)

References 78 publications

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“…ALKBH2 (FGRRES_09872), ALKBH3 (FGRRES_16456), and ALKBH4 (FGRRES_01255 were closely related to human ALKBH3 and Arabidopsis ALKBH2, which are responsible for repairing DNA damage caused by alkylation ( 51 , 52 ). ALKBH5 (FGRRES_20373) was placed sister to the clade containing human ALKBH6, which plays a role in DNA repair ( 53 , 54 ). ALKBH1 (FGRRES_16652) formed a well-supported clade with human and Arabidopsis ALKBH1s, known for their versatile functions in removing methyl groups from DNA/RNA, as well as modifying histone H2A ( 55 – 57 ).…”

Section: Resultsmentioning

confidence: 99%

Phylogenetic and functional analyses of N ⁶ -methyladenosine RNA methylation factors in the wheat scab fungus Fusarium graminearum

Kim,

Hu,

Kang

et al. 2024

mSphere

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In eukaryotes, N 6 -methyladenosine (m 6 A) RNA modification plays a crucial role in governing the fate of RNA molecules and has been linked to various developmental processes. However, the phyletic distribution and functions of genetic factors responsible for m 6 A modification remain largely unexplored in fungi. To get insights into the evolution of m 6 A machineries, we reconstructed global phylogenies of potential m 6 A writers, readers, and erasers in fungi. Substantial copy number variations were observed, ranging from up to five m 6 A writers in early-diverging fungi to a single copy in the subphylum Pezizomycotina, which primarily comprises filamentous fungi. To characterize m 6 A factors in a phytopathogenic fungus Fusarium graminearum , we generated knockout mutants lacking potential m 6 A factors including the sole m 6 A writer MTA1 . However, the resulting knockouts did not exhibit any noticeable phenotypic changes during vegetative and sexual growth stages. As obtaining a homozygous knockout lacking MTA1 was likely hindered by its essential role, we generated MTA1 -overexpressing strains ( MTA1 -OE). The MTA1 -OE5 strain showed delayed conidial germination and reduced hyphal branching, suggesting its involvement during vegetative growth. Consistent with these findings, the expression levels of MTA1 and a potential m 6 A reader YTH1 were dramatically induced in germinating conidia, followed by the expression of potential m 6 A erasers at later vegetative stages. Several genes including transcription factors, transporters, and various enzymes were found to be significantly upregulated and downregulated in the MTA1 -OE5 strain. Overall, our study highlights the functional importance of the m 6 A methylation during conidial germination in F. graminearum and provides a foundation for future investigations into m 6 A modification sites in filamentous fungi. IMPORTANCE N 6 -methyladenosine (m 6 A) RNA methylation is a reversible posttranscriptional modification that regulates RNA function and plays a crucial role in diverse developmental processes. This study addresses the knowledge gap regarding phyletic distribution and functions of m 6 A factors in fungi. The identification of copy number variations among fungal groups enriches our knowledge regarding the evolution of m 6 A machinery in fungi. Functional characterization of m 6 A factors in a phytopathogenic filamentous fungus Fusarium graminearum provides insights into the essential role of the m 6 A writer MTA1 in conidial germination and hyphal branching. The observed effects of overexpressing MTA1 on fungal growth and gene expression patterns of m 6 A factors throughout the life cycle of F. graminearum further underscore the importance of m 6 A modification in conidial germination. Overall, this study significantly advances our understanding of m 6 A modification in fungi, paving the way for future research into its roles in filamentous growth and potential applications in disease control.

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Section: Resultsmentioning

confidence: 99%

Phylogenetic and functional analyses of N ⁶ -methyladenosine RNA methylation factors in the wheat scab fungus Fusarium graminearum

Kim,

Hu,

Kang

et al. 2024

mSphere

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“…Among all the AlkB Homologs, ALKBH6 is the least informed. A recent study has resolved the crystal structure of ALKBH6 (PDB ID: 7VJV) and analyzed its potential biological functions ( 44 ) (see Table 1 ). Human ALKBH6 contains 238 amino acids and, as a member of the AlkB family, also includes the NRL domain for substrate recognition and the conserved DSBH domain, in which His114, Asp116, and His182 stably coordinate the metal ion.…”

Section: The Structures and Biological Functions Of Alkb Homologsmentioning

confidence: 99%

“…Since the crystal structure of ALKBH6 has only been resolved recently, its substrates have yet to be determined. The structure-based interaction partner screening not only identified transcriptional repressors ZMYND11 and ALKBH6 as having unknown interactions in suppressing tumor growth but also explained that histone modifications and nucleic acid modifications have cross-talk in epigenetic regulation ( 44 ). There is insufficient evidence for the substrates it can bind; however, its specific structure indicates the demethylase activity.…”

Section: The Roles Of Alkb Homologs In Cancermentioning

confidence: 99%

The role of demethylase AlkB homologs in cancer

Zhu

2023

Front. Oncol.

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The AlkB family (ALKBH1-8 and FTO), a member of the Fe (II)- and α-ketoglutarate-dependent dioxygenase superfamily, has shown the ability to catalyze the demethylation of a variety of substrates, including DNA, RNA, and histones. Methylation is one of the natural organisms’ most prevalent forms of epigenetic modifications. Methylation and demethylation processes on genetic material regulate gene transcription and expression. A wide variety of enzymes are involved in these processes. The methylation levels of DNA, RNA, and histones are highly conserved. Stable methylation levels at different stages can coordinate the regulation of gene expression, DNA repair, and DNA replication. Dynamic methylation changes are essential for the abilities of cell growth, differentiation, and division. In some malignancies, the methylation of DNA, RNA, and histones is frequently altered. To date, nine AlkB homologs as demethylases have been identified in numerous cancers’ biological processes. In this review, we summarize the latest advances in the research of the structures, enzymatic activities, and substrates of the AlkB homologs and the role of these nine homologs as demethylases in cancer genesis, progression, metastasis, and invasion. We provide some new directions for the AlkB homologs in cancer research. In addition, the AlkB family is expected to be a new target for tumor diagnosis and treatment.

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“…[7][8][9] In humans, the AlkB family contains nine highly conserved members: ALKBH1 through ALKBH8 plus fat mass and obesity-associated protein (FTO). [35,36] However, they show extensive demethylation activity on distinct substrates. Beside ALKBH1, ALKBH5 and FTO catalyze RNA m 6 A demethylation; [37,38] While ALKBH2 and ALKBH3 catalyze m 1 A/N 1 -methyl-dA (1mA) and N 3 -methylcytosine (N 3 -methyl-C, m 3 C)/N 3 -methyl-dC(3mC) demethylation on nucleic acids with their highly conserved amino acid sequences and tertiary protein structures.…”

Section: Introductionmentioning

confidence: 99%

“…In humans, the AlkB family contains nine highly conserved members: ALKBH1 through ALKBH8 plus fat mass and obesity‐associated protein (FTO) [35,36] . However, they show extensive demethylation activity on distinct substrates.…”

Section: Introductionmentioning

confidence: 99%

The Molecular Basis of Human ALKBH3 Mediated RNA N¹‐methyladenosine (m¹A) Demethylation

Zhang,

Duan,

Paduch

et al. 2024

Angew Chem Int Ed

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N1‐methyladenosine (m1A) is a prevalent post‐transcriptional RNA modification, and the distribution and dynamics of the modification play key epitranscriptomic roles in cell development. At present, the human AlkB Fe(II)/α‐ketoglutarate‐dependent dioxygenase family member ALKBH3 is the only known mRNA m1A demethylase, but its catalytic mechanism remains unclear. Here, we present the structures of ALKBH3‐oligo crosslinked complexes obtained with the assistance of a synthetic antibody crystallization chaperone. Structural and biochemical results showed that ALKBH3 utilized two β‐hairpins (β4‐loop‐β5 and β′‐loop‐β′′) and the α2 helix to facilitate single‐stranded substrate binding. Moreover, a bubble‐like region around Asp194 and a key residue inside the active pocket (Thr133) enabled specific recognition and demethylation of m1A‐ and 3‐methylcytidine (m3C)‐modified substrates. Mutation of Thr133 to the corresponding residue in the AlkB Fe(II)/α‐ketoglutarate‐dependent dioxygenase family members FTO or ALKBH5 converted ALKBH3 substrate selectivity from m1A to N6‐methyladenosine (m6A), as did Asp194 deletion. Our findings provide a molecular basis for understanding the mechanisms of substrate recognition and m1A demethylation by ALKBH3. This study is expected to aid structure‐guided design of chemical probes for further functional studies and therapeutic applications.

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Structural insights into the interactions and epigenetic functions of human nucleic acid repair protein ALKBH6

Cited by 14 publications

References 78 publications

Phylogenetic and functional analyses of N ⁶ -methyladenosine RNA methylation factors in the wheat scab fungus Fusarium graminearum

Phylogenetic and functional analyses of N ⁶ -methyladenosine RNA methylation factors in the wheat scab fungus Fusarium graminearum

The role of demethylase AlkB homologs in cancer

The Molecular Basis of Human ALKBH3 Mediated RNA N¹‐methyladenosine (m¹A) Demethylation

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Structural insights into the interactions and epigenetic functions of human nucleic acid repair protein ALKBH6

Cited by 14 publications

References 78 publications

Phylogenetic and functional analyses of N 6 -methyladenosine RNA methylation factors in the wheat scab fungus Fusarium graminearum

Phylogenetic and functional analyses of N 6 -methyladenosine RNA methylation factors in the wheat scab fungus Fusarium graminearum

The role of demethylase AlkB homologs in cancer

The Molecular Basis of Human ALKBH3 Mediated RNA N1‐methyladenosine (m1A) Demethylation

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Product

Resources

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Phylogenetic and functional analyses of N ⁶ -methyladenosine RNA methylation factors in the wheat scab fungus Fusarium graminearum

Phylogenetic and functional analyses of N ⁶ -methyladenosine RNA methylation factors in the wheat scab fungus Fusarium graminearum

The Molecular Basis of Human ALKBH3 Mediated RNA N¹‐methyladenosine (m¹A) Demethylation