Transcriptional collision between convergent genes in budding yeast

Prescott, Elizabeth M.; Proudfoot, Nick J.

doi:10.1073/pnas.132270899

Cited by 237 publications

(214 citation statements)

References 32 publications

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“…Second, antisense mRNAs were suggested to promote the methylation of sense mRNA promoters. And third, the formation of double-stranded RNA hybrids may interfere with further mRNA processing (Wutz et al, 1997;Lai, 2002;Prescott and Proudfoot, 2002;Tufarelli et al, 2003;Lavorgna et al, 2004;Crampton et al, 2006). These models are not mutually exclusive, and more than one of them may apply to the situation of p53 and WRAP53.…”

Section: Discussionmentioning

confidence: 99%

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Bug

Dobbelstein

2011

Oncogene

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Mutant p53 frequently accumulates in cancer cells and promotes tumor cell invasion, as part of its gain of function. Its accumulation is partially due to enhanced stability, but little is known about how the mRNA levels of mutant p53 can be regulated. Likewise, the impact of cancer therapy on the levels of mutant p53 is poorly understood. We show here that the anthracyclines doxorubicin, daunorubicin and epirubicin further increase the amounts of mutant p53 mRNA and protein in cancer cells. Moreover, we show for the first time that the transcription factor E2F1 associates with the promoter DNA of TP53. Upon genotoxic treatment, E2F1 contributed to the expression of mutant p53, both directly and through induction of TAp73. In contrast, the anthracycline idarubicin and also another topoisomerase inhibitor, etoposide, failed to increase the levels of p53 mRNA, despite their ability to induce the synthesis of TAp73 mRNA. Instead, a natural antisense transcript of TP53, WRAP53, was strongly augmented by idarubicin and etoposide, but only less so by the other anthracyclines under study. RNA corresponding to the first exon of WRAP53 was mainly found in cell nuclei and it reduced the levels of mutant p53. Taken together, this suggests a reciprocal activation pattern of TP53 and WRAP53 by different chemotherapeutics. Reducing the levels of mutant p53 by small-interfering RNA increased chemosensitivity, and idarubicin prevented cell survival more efficiently than the mutant p53-inducing doxorubicin. We conclude that even closely related anthracyclines induce the synthesis of different, opposing transcripts from the TP53 locus. When using these drugs for cancer therapy, the increased levels of mutant p53 may augment its gain of function and thus favor unwanted chemoresistance and tumor progression.

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Section: Discussionmentioning

confidence: 99%

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Bug

Dobbelstein

2011

Oncogene

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“…It is unlikely that two overlapping transcriptional units could be transcribed concomitantly by the RNA pol II machinery. Such effects have been well studied with respect to the GAL10 and GAL7 genes in S. cerevisiae (Prescott and Proudfoot 2002). When arranged convergently, but not overlapping, both genes are transcribed at normal levels.…”

Section: Transcriptional Interferencementioning

confidence: 99%

Eukaryotic regulatory RNAs: an answer to the ‘genome complexity’ conundrum

Prasanth¹,

Spector²

2007

Genes Dev.

363

305

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A large portion of the eukaryotic genome is transcribed as noncoding RNAs (ncRNAs). While once thought of primarily as "junk," recent studies indicate that a large number of these RNAs play central roles in regulating gene expression at multiple levels. The increasing diversity of ncRNAs identified in the eukaryotic genome suggests a critical nexus between the regulatory potential of ncRNAs and the complexity of genome organization. We provide an overview of recent advances in the identification and function of eukaryotic ncRNAs and the roles played by these RNAs in chromatin organization, gene expression, and disease etiology.

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“…The third model, transcriptional interference, is based on the concept that convergent transcription by RNA polymerase II on two overlapping genes results in "transcriptional collision," thus inhibiting transcript elongation (20,21). The aII transcript can be detected with a RT-PCR-based approach at numerous sites along the entire 27-kb length of the IIa MHC gene, from the IIa/IIx intergenic region to upstream of the IIa gene and into its regulatory promoter region.…”

Section: Potential Mechanisms Of Mhc Gene Regulation By Antisensementioning

confidence: 99%

“…NATs have been identified recently as being involved in the regulation of gene expression in eukaryotes (15,16), and NATs have been identified in the human genome (17)(18)(19). Their involvement in gene regulation is quite variable, and no generalized mechanism exists, but examples include transcription interference (20,21), RNA editing (22), and inhibition of splicing (23). NAT prevalence in the human genome has only recently become appreciated.…”

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confidence: 99%

Dynamics of Myosin Heavy Chain Gene Regulation in Slow Skeletal Muscle

Pandorf

Haddad

Roy

et al. 2006

Journal of Biological Chemistry

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The evolutionarily conserved order of the skeletal muscle myosin heavy chain (MHC) genes and their close tandem proximity on the same chromosome are intriguing and may be important for their coordinated regulation. We investigated type II MHC gene regulation in slow-type muscle fibers undergoing a slow to fast MHC transformation in response to inactivity, 7 days after spinal cord isolation (SI) in rats. We examined the transcriptional products of both the sense and antisense strands across the IIa-IIx-IIb MHC gene locus. A strand-specific reverse transcription (RT)-PCR approach was utilized to study the expression of the mRNA, the primary transcript (pre-mRNA), the antisense RNA overlapping the MHC genes, and both the intergenic sense and antisense RNAs. Results showed that the mRNA and pre-mRNA of each MHC had a similar response to SI, suggesting regulation of these genes at the transcriptional level. In addition, we detected previously unknown antisense strand transcription that produced natural antisense transcripts (NATs). RT-PCR mapping of the RNA products revealed that the antisense activity resulted in the formation of three major products: aII, xII, and bII NATs (antisense products of the IIa, IIx, and IIb genes, respectively). The aII NAT begins in the IIa-IIx intergenic region in close proximity to the IIx promoter, extends across the 27-kb IIa MHC gene, and continues to the IIa MHC gene promoter. The expression of the aII NAT was significantly up-regulated in muscles after SI, was negatively correlated with IIa MHC gene expression, and was positively correlated with IIx MHC gene expression. The exact role of the aII NAT is not clear; however, it is consistent with the inhibition of IIa MHC gene transcription. In conclusion, NATs may mediate cross-talk between adjacent genes, which may be essential to the coordinated regulation of the skeletal muscle MHC genes during dynamic phenotype shifts.Skeletal muscle is highly adaptable when subjected to altered loading and hormone states. Its size, metabolic makeup, and contractile properties can all be altered to optimize function (1). Variability in contractile properties is achieved mainly by diversification in the motor protein myosin heavy chain (MHC), 2 where different isoforms are encoded by distinct genes (1, 2). Of this family of eight MHC genes, six are tandemly linked and span ϳ420 kb in the rat on chromosome 10, with embryonic MHC situated at the most 5Ј end, sequentially followed by IIa, IIx, IIb, neonatal, and extraocular MHC. ␤ (or type I) and ␣ MHCs are located tandemly on separate chromosomes (chromosome 14 in the rat); they span ϳ50 kb and are separated by 4.5 kb. Interestingly, the genomic order and orientation on the chromosomes of the MHC genes are conserved in all mammalian species, leading researchers to suspect that this organization might be an important feature in the strategy for the coordinated regulation of these genes (2-5).Types I, IIa, IIx, and IIb, in respective order of increasing ATPase activity, are the four predominately exp...

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Transcriptional collision between convergent genes in budding yeast

Cited by 237 publications

References 32 publications

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

Eukaryotic regulatory RNAs: an answer to the ‘genome complexity’ conundrum

Dynamics of Myosin Heavy Chain Gene Regulation in Slow Skeletal Muscle

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