Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FRAXE fragile site associated mental retardation (FRAXE MR) belongs to a group of non-syndromic X-linked mental retardation. Two genes, FMR2 and FMR3 (likely a non-coding RNA) are transcribed from the FRAXE CpG island in the opposite directions. While the contribution of the FMR2 gene to FRAXE MR has been demonstrated, the role of the FMR3 gene is not known. We have screened 441 Brazilian mentally handicapped males for CCG repeat expansions in the FMR2 gene and identified a boy with a mutation (c.-414_-357del58) immediately distal to the FRAXE CCG repeat. We have established a skin fibroblast cell line from this patient and tested expression of both FMR2 and FMR3 genes. Reverse transcriptase PCR studies on the FMR2 and FMR3 genes showed that only the FMR3 gene transcription was abolished, suggesting a possible causal relationship between the lack of FMR3 expression and mental retardation in this patient. In the literature, there have been few deletions described near the FRAXE CCG repeat, but none was followed with expression studies. This is the first study showing missing expression in the FMR3 gene with normal FMR2 transcription leading to FRAXE mutation-likely phenotype. The FMR3 gene is likely a non-coding RNA gene. So far all individuals with FRAXE CCG repeat expansions and cytogenetically detectable FRAXE fragile site have both FMR2 and FMR3 gene expression abolished. Although the function of the FMR3 gene is not known, our present study together with previous studies on FRAXE MR suggest that it may play role in the processes underpinning normal learning and memory.
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PMID:Lack of FMR3 expression in a male with non-syndromic mental retardation and a microdeletion immediately distal to FRAXE CCG repeat. 1646 43

AF4 gene, frequently translocated with mixed-lineage leukemia (MLL) in childhood acute leukemia, encodes a putative transcriptional activator of the AF4/LAF4/FMR2 (ALF) protein family previously implicated in lymphopoiesis and Purkinje cell function in the cerebellum. Here, we provide the first evidence for a direct role of AF4 in the regulation of transcriptional elongation by RNA polymerase II (Pol II). We demonstrate that mouse Af4 functions as a positive regulator of Pol II transcription elongation factor b (P-TEFb) kinase and, in complex with MLL fusion partners Af9, Enl and Af10, as a mediator of histone H3-K79 methylation by recruiting Dot1 to elongating Pol II. These pathways are interconnected and tightly regulated by the P-TEFb-dependent phosphorylation of Af4, Af9 and Enl which controls their transactivation activity and/or protein stability. Consistently, increased levels of phosphorylated Pol II and methylated H3-K79 are observed in the ataxic mouse mutant robotic, an over-expression model of Af4. Finally, we confirm the functional relevance of Af4, Enl and Af9 to the regulation of gene transcription as their over-expression strongly stimulates P-TEFb-dependent transcription of a luciferase reporter gene. Our findings uncover a central role for these proteins in the regulation of transcriptional elongation and coordinated histone methylation, providing valuable insight into their contribution to leukemogenesis and neurodegeneration. Since these activities likely extend to the entire ALF protein family, this study also significantly inputs our understanding of the molecular basis of FRAXE mental retardation syndrome in which FMR2 expression is silenced.
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PMID:The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. 1713 74

R-loops have been described at immunoglobulin class switch sequences, prokaryotic and mitochondrial replication origins, and disease-associated (CAG)n and (GAA)n trinucleotide repeats. The determinants of trinucleotide R-loop formation are unclear. Trinucleotide repeat expansions cause diseases including DM1 (CTG)n, SCA1 (CAG)n, FRAXA (CGG)n, FRAXE (CCG)n and FRDA (GAA)n. Bidirectional convergent transcription across these disease repeats can occur. We find R-loops formed when CTG or CGG and their complementary strands CAG or CCG were transcribed; GAA transcription, but not TTC, yielded R-loops. R-loop formation was sensitive to DNA supercoiling, repeat length, insensitive to repeat interruptions, and formed by extension of RNA:DNA hybrids in the RNA polymerase. R-loops arose by transcription in one direction followed by transcription in the opposite direction, and during simultaneous convergent bidirectional transcription of the same repeat forming double R-loop structures. Since each transcribed disease repeat formed R-loops suggests they may have biological functions.
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PMID:Determinants of R-loop formation at convergent bidirectionally transcribed trinucleotide repeats. 2105 37