A complex molecular switch directs stress-induced cyclin C nuclear release through SCF<sup>Grr1</sup>-mediated degradation of Med13

Stieg, David C.; Willis, Stephen D.; Ganesan, Vidyaramanan; Ong, Kai Li; Scuorzo, Joseph; Song, Mia; Grose, Julianne H.; Strich, Randy; Cooper, Katrina F.

doi:10.1091/mbc.e17-08-0493

Cited by 36 publications

(56 citation statements)

References 86 publications

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“…Notably, it is also previously documented that fis1yeast is still capable of undergoing mitochondrial fragmentation which may be a reason for the lack of the TDP-43 toxicity rescue in the fis1 yeast. We also observed here that the deletion of the MED13 gene that encodes for the Med13 protein which is essential for the nuclear retention of Cyclin C failed to rescue the TDP-43 toxicity [89,90].…”

Section: Discussionsupporting

confidence: 64%

“…This provides sufficient dwell time on mitochondria for BAX to be recognized by the BH3 containing proteins leading to initiation of PCD in the mammalian cell line [88]. Since Cyclin C translocation from the nucleus to the cytoplasm is a conserved process from the yeast to humans, this finding of TDP-43-induced Cyclin C translocation in yeast may have direct relevance to the ALS pathology [83,85,88,91,92]. Therefore, targeting the TDP-43 expression-induced oxidative stress and the Cyclin C translocation may have potentially fruitful consequences towards finding of the ALS therapeutic targets.…”

Section: Discussionmentioning

confidence: 92%

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Role ofCNC1gene in TDP-43 aggregation-induced oxidative stress-mediated cell death inS. cerevisiaemodel of ALS

Bharathi

Girdhar

Patel

2020

Preprint

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TDP-43 is a multi-functional ribonucleoprotein that is also found deposited as hyperphosphorylated and ubiquitinated TDP-43 inclusions in the brain and spinal cord of the patients of the motor neuron diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Till date, how the cell death ensues is not fully deciphered although several molecular mechanisms of the TDP-43 toxicity such as impairments of endocytosis and chromatin remodelling, mis-regulations of autophagy and proteasome function, mis-localization to the mitochondria and generation of oxidative stress etc., have been proposed. A predominantly nuclear protein, Cyclin C, can regulate the oxidative stress response by affecting the transcription of stress response genes and also by translocation to the cytoplasm for the activation of the mitochondrial fragmentation-dependent cell death pathway. Using the well-established yeast model of TDP-43 aggregation and toxicity, we examined here whether upon TDP-43 aggregation, the cell survival depends on the presence of the CNC1 gene that encodes Cyclin C protein or other genes that encode proteins that function in conjunction with Cyclin C, such as the DNM1, FIS1 and MED13 genes. We found that the TDP-43 toxicity is significantly reduced in the yeast deleted for the CNC1 or DNM1 genes. Importantly, the rescue of TDP-43 toxicity in these yeast deletion backgrounds required the presence of functional mitochondria. Also, the deletion of YBH3 gene, which encodes for a protein involved in the mitochondria-dependent apoptosis, also reduced the TDP-43 toxicity. Furthermore, Cyclin C-YFP was observed to localize from the nucleus to the cytoplasm in response to the TDP-43 co-expression. Also, this cytoplasmic localization of Cyclin C was prevented by the addition of an anti-oxidant molecule, N-acetyl-cysteine.Taken together, our data suggest that Cyclin C, Dnm1 and Ybh3 proteins are important in mediating the TDP-43-induced oxidative stress-mediated cell death in the S. cerevisiae model.3

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 92%

Role ofCNC1gene in TDP-43 aggregation-induced oxidative stress-mediated cell death inS. cerevisiaemodel of ALS

Bharathi

Girdhar

Patel

2020

Preprint

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“…Our yeast studies revealed a Cdk8 phosphorylation is required for Med13 destruction and subsequent cyclin C nuclear release into the cytoplasmic (28). To test whether Cdk8 activity is required for the changes observed for the CKM promoter occupancy in mammalian cells, we directly compared transcription and promoter occupancy in Ccnc -/mutants and WT cells were treated with the Cdk8 kinase inhibitor Senexin A (37).…”

Section: Cyclin C Regulates Transcription Both Dependent and Independmentioning

confidence: 99%

Cyclin C promoter occupancy directs changes in stress-dependent transcription

Stieg

Cooper

Strich

2020

Preprint

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The Cdk8 kinase module (CKM) is a detachable Mediator subunit composed of cyclin C, and one each of paralogs Cdk8/Cdk19, Med12/Med12L and Med13/Med13L. In addition to regulating transcription, a portion of cyclin C also leaves the nucleus following cytotoxic stress to induce mitochondrial fragmentation and apoptosis. Our previous RNA-seq studies demonstrated that cyclin C represses a subset of hydrogen peroxide-induced genes under normal conditions, while also being required for the full induction of other loci following stress. Here, we show that cyclin C directs this transcriptional re-programing through changes in its promoter occupancy. Following peroxide stress, cyclin C promoter occupancy increased for genes it activates while decreasing at loci it represses under normal conditions. Promoter occupancy of other CKM components generally mirrored cyclin C indicating that the CKM moves as a single unit. However, CKM integrity appeared compromised at a subset of repressed promoters suggesting a source of cyclin C that is targeted for nuclear release. Interestingly, mTOR inhibition induced a new pattern of cyclin C promoter occupancy indicating that this control is fine-tuned to the individual stress. Using inhibitors, we found that Cdk8 kinase activity is not required for CKM movement or repression but was necessary for full gene activation. In conclusion, this study revealed that different stress stimuli elicit specific changes in CKM promoter occupancy correlating to altered transcriptional outputs. Finally, although CKM components were recruited or expelled from promoters as a unit, heterogeneity was observed at individual promoters suggesting a mechanism to generate gene- and stress-specific responses.

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“…Precocious cyclin C nuclear release sensitizes D316 cells to an anti-cancer drug Cyclin C exhibits stress-induced nuclear release in budding yeast (Cooper et al, 2014(Cooper et al, , 2012 similar to that observed in mammalian cells (Wang et al, 2015). Subsequent studies revealed that the yeast cyclin C is retained in the nucleus through interaction with the Med13 protein (Khakhina et al, 2014;Stieg et al, 2018). The binding domain on cyclin C directing this interaction is termed the holoenzyme-associating domain or HAD (Cooper and Strich, 1999).…”

Section: Resultsmentioning

confidence: 90%

Synergistic repression of thyroid hyperplasia by cyclin C and Pten

Ježek

Wang

Yan

et al. 2019

Journal of Cell Science

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The cyclin C-Cdk8 kinase has been identified as both a tumor suppressor and an oncogene depending on the cell type. The genomic locus encoding cyclin C (Ccnc) is often deleted in aggressive anaplastic thyroid tumors. To test for a potential tumor suppressor role for cyclin C, Ccnc alone, or Ccnc in combination with a previously described thyroid tumor suppressor Pten, was deleted late in thyroid development. Although mice harboring individual Pten or Ccnc deletions exhibited modest thyroid hyperplasia, the double mutant demonstrated dramatic thyroid expansion resulting in animal death by 22 weeks. Further analysis revealed that Ccnc thyr−/− tissues exhibited a reduction in signal transducer and activator of transcription 3 (Stat3) phosphorylation at Ser727. Further analysis uncovered a post-transcriptional requirement of both Pten and cyclin C in maintaining the levels of the p21 and p53 tumor suppressors (also known as CDKN1A and TP53, respectively) in thyroid tissue. In conclusion, these data reveal the first tumor suppressor role for cyclin C in a solid tumor model. In addition, this study uncovers new synergistic activities of Pten and cyclin C to promote quiescence through maintenance of p21 and p53.

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A complex molecular switch directs stress-induced cyclin C nuclear release through SCF^Grr1-mediated degradation of Med13

Cited by 36 publications

References 86 publications

Role ofCNC1gene in TDP-43 aggregation-induced oxidative stress-mediated cell death inS. cerevisiaemodel of ALS

Role ofCNC1gene in TDP-43 aggregation-induced oxidative stress-mediated cell death inS. cerevisiaemodel of ALS

Cyclin C promoter occupancy directs changes in stress-dependent transcription

Synergistic repression of thyroid hyperplasia by cyclin C and Pten

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A complex molecular switch directs stress-induced cyclin C nuclear release through SCFGrr1-mediated degradation of Med13

Cited by 36 publications

References 86 publications

Role ofCNC1gene in TDP-43 aggregation-induced oxidative stress-mediated cell death inS. cerevisiaemodel of ALS

Role ofCNC1gene in TDP-43 aggregation-induced oxidative stress-mediated cell death inS. cerevisiaemodel of ALS

Cyclin C promoter occupancy directs changes in stress-dependent transcription

Synergistic repression of thyroid hyperplasia by cyclin C and Pten

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A complex molecular switch directs stress-induced cyclin C nuclear release through SCF^Grr1-mediated degradation of Med13