Comments:

Belongs to AlkB family of nonheme Fe(II)/a-ketoglutarate (a-KG)-dependent dioxygenases (same protein family as FTO demethylase). In vitro demethylates m6A in RNA and DNA however m6A in mRNA is a physiologically relevant substrate of ALKBH5 inside cells. Strongly prefers single-stranded substrates, exhibits an almost unnoticeable demethylation activity toward m6A in a 26-mer double-stranded RNA. ALKBH5 and its demethylation activity play important roles in mRNA export as well as roles in the association of the nuclear speckle proteins and RNA metabolism. The Alkbh5 deficiency leads to aberrant spermatogenesis and apoptosis in mouse testes. Transcriptome analysis revealed differentially expressed genes associated with spermatogenesis and the p53 functional interaction network, in line with the impaired fertility observed for the Alkbh5-/- mouse.

Protein sequence:

Enzymatic activities:

Reaction	Substrate	Type	Position
m6A:A	mRNA (m)		many

Diseases connected to this enzyme:

Description	Reaction	Disease Name
Increased KCNK15-AS1 lncRNA m6A methylation level is negatively correlated with KCNK15-AS1 expression and it sustains the proliferation, invasion and migration of pancreatic cancer cells. Decreased expression of ALKBH5 in pancreatic cancer cell determines an increased methylation of KCNK15-AS1 lncRNA, a decreased KCNK15-AS1 expression and an increased proliferation, migration and invasion of pancreatic cancer cells.	A:m6A	Pancreatic cancer
ALKBH5 decreases WIF-1 mRNA m6A levels and thus increases WIF protein levels. The upregulation of WIF-1 inhibits Wnt pathway and its downstream targets, leading to the inhibition of pancreatic tumorigenesis and sensitization to chemotherapy. Thus, the downregulation of ALKBH5 in pancreatic cancer, induces PDAC cell proliferation, migration, invasion, tumorigenesis, and metastasis in vitro and in vivo.	A:m6A	Pancreatic cancer
Intermittent hipoxia (HI) promotes the expression of ALKBH5 in lung adenocarcinoma. The m6A demethylase ALKBH5 affects the proliferation and invasion of lung adenocarcinoma cells under IH by downregulating m6A modification on FOXM1 mRNA and by promoting FOXM1 expression. FOXM1 has been reported to play an important role in cell proliferation, cell cycle, cell differentiation, angiogenesis and metastasis, and also with cisplatin-based chemotherapy resistance	A:m6A	Non-small cell lung cancer
ALKBH5 is upregulated in the NSCLC tissue and cells. ALKBH5 induces the demethylation of TIMP3 transcript to repress its mRNA stability leading to NSCLC tumor progression	A:m6A	Non-small cell lung cancer
rs12936694 from the m6A demethylase gene ALKBH5 showed allelic and genotypic association to major depressive disorder	A:m6A	Major depressive disorder
Mutations found in m6A regulatory genes are associated with lower OS and EFS rates in patients with AML ( Acute myeloid Leukemia) and presence of p53 mutations.	A:m6A	Leukemia
Increased m6A methylation protects against GSCs self-renewal, proliferation and tumorigenesis. The increased ALKBH5 expression in GSCs is associated to a decreased methylation of FOXM1 pre-mRNA.	A:m6A	Glioblastoma
ALKBH5 and NEAT1 are upregulated in gastric cancer. The m6A eraser ALKBH5 downregulates NEAT1 m6A levels. With decreases in NEAT1 methylation, NEAT1 is upregulated and promotes the malignant phenotype of GC by acting synergistically with EZH2	A:m6A	Gastric cancer
m6A levels are decreased in immortalized and oncogenically transformed human mammary epithelial cells. The levels of METTL3 are descresed and ALKBH5 are increased. Overexpression of METTL3 and METTL14 and knockdown of ALKBH5 results in increased proliferation and migaration of immortalized cells. m6A levels may be downregulated in immortalized cells. Hypoxia increased m6A levels throgh mechanisms that are independent of METTL3, METTL14 and ALKBH5 expression levels. Increases of m6A levels in hypoxia are regulated by HIF.	A:m6A	Breast cancer
m6A modification control the mRNA expression level of NANOG in some breast cancer cell lines. ALKBH5 plays critical role in mediating NANOG expression and BCSC specification and/or maintenance within the hypoxic microenvironment of human breast cancer orthotopic tumors. Mediates (together with Hypoxia-inducible factors (HIFs)) m6A demetylation of NANOG in hypoxic conditions.	A:m6A	Breast cancer
m6A inhibits breast cancer (BC) cell viability, the ability of MDA-MB-231 cells to form colonies and suppressed cell migratory abilities resulting in an overall effect of inhibition of BC growth and metastasis. Reduced expression of m6A is associated with poor prognostic in patient. Functionally, reducing m6A expression by overexpressing METTL14 and/or knockdown of ALKBH5 could inhibit breast cell viability, colony formation and cell migration.	A:m6A	Breast cancer
"m6A levels are reduced in breast cancer samples due to a decrease in m6A methylases expression and an increase in demethylases expression; expression levels of METTL3, METTL14, WTAP and FTO were correlated with poor survival and cancer progression; m6A higher levels suppress cancer cell viability, inhibit MDA-MB-231 colony-formation abilities and cell migratory abilities.Expression levels of writers and readers differes according to the subtype of breast cancer ( luminal A/B vs. triple negative)."	A:m6A	Breast cancer

Publications:

Title	Authors	Journal	Details	PubMed Id	DOI
ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility.	Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vagbo CB, Shi Y, Wang WL, Song SH, Lu Z, Bosmans RP, Dai Q, Hao YJ, Yang X, Zhao WM, Tong WM, Wang XJ, Bogdan F, Furu K, Fu Y, Jia G, Zhao X, Liu J, Krokan HE, Klungland A, Yang YG, He C...	Mol Cell	[details]	23177736	-
Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1alpha (HIF-1alpha).	Thalhammer A, Bencokova Z, Poole R, Loenarz C, Adam J, O'Flaherty L, Schodel J, Mole D, Giaslakiotis K, Schofield CJ, Hammond EM, Ratcliffe PJ, Pollard PJ...	PLoS One	[details]	21264265	-
Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation.	Aik W, Scotti JS, Choi H, Gong L, Demetriades M, Schofield CJ, McDonough MA...	Nucleic Acids Res	[details]	24489119	-
Crystal Structures of Human RNA Demethylase Alkbh5 Reveal Basis for Substrate Recognition.	Feng C, Liu Y, Wang G, Deng Z, Zhang Q, Wu W, Tong Y, Cheng C, Chen Z...	J Biol Chem	[details]	24616105	-
Molecular biology. Internal mRNA methylation finally finds functions.	Nilsen TW...	Science	[details]	24626918	-
Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single stranded m6A RNA demethylation.	Xu C, Liu K, Tempel W, Demetriades M, Aik W, Schofield CJ, Min J...	J Biol Chem	[details]	24778178	-

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