Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial DNA (mtDNA) depletion syndrome (MDS; MIM 251880) is a prevalent cause of oxidative phosphorylation disorders characterized by a reduction in mtDNA copy number. The hitherto recognized disease mechanisms alter either mtDNA replication (POLG (ref. 1)) or the salvage pathway of mitochondrial deoxyribonucleosides 5'-triphosphates (dNTPs) for mtDNA synthesis (DGUOK (ref. 2), TK2 (ref. 3) and SUCLA2 (ref. 4)). A last gene, MPV17 (ref. 5), has no known function. Yet the majority of cases remain unexplained. Studying seven cases of profound mtDNA depletion (1-2% residual mtDNA in muscle) in four unrelated families, we have found nonsense, missense and splice-site mutations and in-frame deletions of the RRM2B gene, encoding the cytosolic p53-inducible ribonucleotide reductase small subunit. Accordingly, severe mtDNA depletion was found in various tissues of the Rrm2b-/- mouse. The mtDNA depletion triggered by p53R2 alterations in both human and mouse implies that p53R2 has a crucial role in dNTP supply for mtDNA synthesis.
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PMID:Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. 1753 60

While the therapeutic activity of the deoxycytidine analogue decitabine is thought to reflect its ability to reactivate methylation-silenced genes, this agent is also known to trigger p53-dependent DNA damage responses. Here, we report that p53-inducible ribonucleotide reductase (p53R2/RRM2B) is a robust transcriptional target of decitabine. In cancer cells, decitabine treatment induces p53R2 mRNA expression, protein expression, and promoter activity in a p53-dependent manner. The mechanism of p53R2 gene induction by decitabine does not seem to be promoter DNA hypomethylation, as the p53R2 5' CpG island is hypomethylated before treatment. Small interfering RNA (siRNA) targeting of DNA methyltransferase 1 (DNMT1) in wild-type p53 cells leads to genomic DNA hypomethylation but does not induce p53R2, suggesting that DNMT/DNA adduct formation is the molecular trigger for p53R2 induction. Consistent with this idea, only nucleoside-based DNMT inhibitors that form covalent DNA adducts induce p53R2 expression. siRNA targeting of p53R2 reduces the extent of cell cycle arrest following decitabine treatment, supporting a functional role for p53R2 in decitabine-mediated cellular responses. To determine the clinical relevance of p53R2 induction, we measured p53R2 expression in bone marrow samples from 15 myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML) patients undergoing decitabine therapy. p53R2 mRNA and protein were induced in 7 of 13 (54%) and 6 of 9 (67%) patients analyzed, respectively, despite a lack of methylation changes in the p53R2 promoter. Most notably, there was a significant association (P = 0.0047) between p53R2 mRNA induction and clinical response in MDS/AML. These data establish p53R2 as a novel hypomethylation-independent decitabine gene target associated with clinical response.
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PMID:p53-inducible ribonucleotide reductase (p53R2/RRM2B) is a DNA hypomethylation-independent decitabine gene target that correlates with clinical response in myelodysplastic syndrome/acute myelogenous leukemia. 1901 Sep 10