Hyperphosphorylation of RNA Polymerase II in Response to Topoisomerase I Cleavage Complexes and Its Association with Transcription- and BRCA1-dependent Degradation of Topoisomerase I

Sordet, Olivier; Larochelle, Stéphane; Nicolas, Estelle; Stevens, Ellen V.; Zhang, Chao; Shokat, Kevan M.; Fisher, Robert P; Pommier, ﻿Yves

doi:10.1016/j.jmb.2008.06.028

Cited by 59 publications

(65 citation statements)

References 53 publications

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“…That the Pfu DNA polymerase used in the LRPCR analysis was unable to amplify across DNA breaks has some important consequences. Both mammalian DNA and RNA polymerases are unable to read across DNA breaks (109). As well, these polymerases are also unable to progress when blocked by a topoisomerase-DNA complex (109).…”

Section: Discussionmentioning

confidence: 99%

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Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Hicks

Labinskyy

Piteo

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat. Am J Physiol Heart Circ Physiol 304: H903-H915, 2013. First published February 1, 2013 doi:10.1152/ajpheart.00567.2012.-Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Mitochondrial oxidant stress has been accepted as the singular cause of mitochondrial DNA (mtDNA) damage as an underlying cause of mitochondrial dysfunction. However, separate from a direct effect on mtDNA integrity, diabetic-induced increases in oxidant stress alter mitochondrial topoisomerase function to propagate mtDNA mutations as a contributor to mitochondrial dysfunction. Both glucose-challenged neonatal cardiomyocytes and the diabetic GotoKakizaki (GK) rat were studied. In both the GK left ventricle (LV) and in cardiomyocytes, chronically elevated glucose presentation induced a significant increase in mtDNA damage that was accompanied by decreased mitochondrial function. TTGE analysis revealed a number of base pair substitutions in the 3' end of COX3 from GK LV mtDNA that significantly altered the protein sequence. Mitochondrial topoisomerase DNA cleavage activity in isolated mitochondria was significantly increased in the GK LV compared with Wistar controls. Both hydroxycamptothecin, a topoisomerase type 1 inhibitor, and doxorubicin, a topoisomerase type 2 inhibitor, significantly exacerbated the DNA cleavage activity of isolated mitochondrial extracts indicating the presence of multiple functional topoisomerases in the mitochondria. Mitochondrial topoisomerase function was significantly altered in the presence of H 2O2 suggesting that separate from a direct effect on mtDNA, oxidant stress mediated type II diabetesinduced alterations of mitochondrial topoisomerase function. These findings are significant in that the activation/inhibition state of the mitochondrial topoisomerases will have important consequences for mtDNA integrity and the well being of the diabetic myocardium. diabetic cardiomyopathy; type 2 diabetes; mitochondrial DNA damage; mitochondrial dysfunction CARDIOVASCULAR DISEASE is responsible for a higher incidence of mortality in diabetics than the general population. Diabetic cardiomyopathy (DCM) is characterized by the development of a myopathy that manifests initially as diastolic dysfunction, but evolves into increased cavitary dilation and mural thinning, which is reflective of decompensated eccentric hypertrophy. DCM is considered to be independent of atherosclerosis or hypertension but is exacerbated by either (94). Mitochondrial dysfunction has long been known to have a significant role in the development and complications of DCM (32,46,66,82,92). Mitochondrial dysfunction is also associated with other pathologies including cancer, skeletal muscle disorders, and neurodegenerative diseases such as Wolfram syndrome or Leber's hereditary optic neuropathy (LHON) (18,36,54,104).Separate from inborn errors, mitochondrial DNA (mtDNA) mutations are thought to accumul...

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Section: Discussionmentioning

confidence: 99%

“…Both mammalian DNA and RNA polymerases are unable to read across DNA breaks (109). As well, these polymerases are also unable to progress when blocked by a topoisomerase-DNA complex (109). Thus both replication and transcription may suffer as a function of mtDNA damage and altered topoisomerase activity.…”

Section: Discussionmentioning

confidence: 99%

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Hicks

Labinskyy

Piteo

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

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“…21,37,59 UV-induced Rbp1 CTD hyper-phosphorylation decreases the speed of transcription elongation, thereby increasing the inclusion of alternative exons in the transcripts of caspase 9, Bcl-x and potentially other apoptosis-related genes. 21 Decreased elongation rate may also explain the induction, by UV and CPT, of NMD-target splice variants in a subset of genes encoding SFs, and may have an even wider impact, as suggested by a recent genome-wide analysis of exon inclusion upon elongation inhibition.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

The emerging role of pre-messenger RNA splicing in stress responses: Sending alternative messages and silent messengers

Dutertre¹,

Sanchez²,

Barbier³

et al. 2011

RNA Biology

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A lternative splicing (AS) of premessenger RNAs is a major process contributing to both transcriptome and proteome diversity in various physiological and pathological situations. There is also accumulating evidence that various stresses impact on AS. In particular, recent analyses of the transcriptome reveal large numbers of AS events that are regulated by genotoxic stress inducers like radiations and chemotherapeutic agents. Many AS events have the potential to affect the relative production of protein isoforms with different activities, as shown in the case of several genes involved in apoptosis. There is also increasing evidence that stresses induce "non-productive" splice variants, leading to a decrease in gene expression levels or preventing increases in protein levels despite transcriptional stimulation. This is typically achieved by the production of splice variants that are subject to nonsense-mediated decay. In addition, recent studies suggest that pre-mRNA splicing efficiency or fidelity may be altered by stresses. For example, various genotoxic agents induce multiple exon skipping in MDM2 transcripts, thereby preventing the production of the main p53-ubiquitin ligase and favoring p53 activity in response to genotoxic agents. In terms of mechanisms, stresses can impact on pre-mRNA splicing by inducing post-translational modifications and subcellular redistribution of splicing factors, or by targeting the communication between the splicing and transcription

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“…Transcriptional stalling is associated with hyperphosphorylation of the largest subunit RPB1 of the RNA polymerase 2 holo-complex (pRPB1, henceforward referred to as pPOLR2A) [42]. POLR2A hyperphosphorylation signals increased proteolytic removal of arrested POLR2A complexes to bypass stalled transcription and repair transcription-associated DNA breaks [43,44]. Phosphorylated POLR2A (pPOLR2A) had markedly increased between t = 0 and 3 days pid, both in shcon and in shBmi1 cells and pPOLR2A remained high throughout TA ( Figure 6C).…”

Section: Increased Polr2 Phosphorylation and Stalled Transcription Fomentioning

confidence: 99%

PRC1 Prevents Replication Stress during Chondrogenic Transit Amplification

et al. 2017

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Transit amplification (TA), a state of combined, rapid proliferative expansion and differentiation of stem cell-descendants, remains poorly defined at the molecular level. The Polycomb Repressive Complex 1 (PRC1) protein BMI1 has been localized to TA compartments, yet its exact role in TA is unclear. PRC1 proteins control gene expression, cell proliferation and DNA-damage repair. Coordination of such DNA-templated activities during TA is predicted to be crucial to support DNA replication and differentiation-associated transcriptional programming. We here examined whether chondrogenesis provides a relevant biological context for synchronized coordination of these chromatin-based tasks by BMI1. Taking advantage of a prominently featuring TA-phase during chondrogenesis in vitro and in vivo, we here report that TA is completely dependent on intact PRC1 function. BMI1-depleted chondrogenic progenitors rapidly accumulate double strand DNA breaks during DNA replication, present massive non-H3K27me3-directed transcriptional deregulation and fail to undergo chondrogenic TA. Genome-wide accumulation of Topoisomerase 2α and Geminin suggests a model in which PRC1 synchronizes replication and transcription during rapid chondrogenic progenitor expansion. Our combined data reveals for the first time a vital cell-autonomous role for PRC1 during chondrogenesis. We provide evidence that chondrocyte hyper-replication and hypertrophy represent a unique example of programmed senescence in vivo. These findings provide new perspectives on PRC1 function in development and disease.

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Hyperphosphorylation of RNA Polymerase II in Response to Topoisomerase I Cleavage Complexes and Its Association with Transcription- and BRCA1-dependent Degradation of Topoisomerase I

Cited by 59 publications

References 53 publications

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

The emerging role of pre-messenger RNA splicing in stress responses: Sending alternative messages and silent messengers

PRC1 Prevents Replication Stress during Chondrogenic Transit Amplification

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