Abstract
Following exposure to cytotoxic agents, cellular damage is first recognized by a variety of sensor mechanisms. Thenceforth, the damage signal is transduced to the nucleus to install the correct gene expression program including the induction of genes whose products either detoxify destructive compounds or repair the damage they cause. Next, the stress signal is disseminated throughout the cell to effect the appropriate changes at organelles including the mitochondria. The mitochondria represent an important signaling platform for the stress response. An initial stress response of the mitochondria is extensive fragmentation. If the damage is prodigious, the mitochondria fragment (fission) and lose their outer membrane integrity leading to the release of pro-apoptotic factors necessary for programmed cell death (PCD) execution. As this complex biological process contains many moving parts, it must be exquisitely coordinated as the ultimate decision is life or death. The conserved C-type cyclin plays an important role in executing this molecular Rubicon by coupling changes in gene expression to mitochondrial fission and PCD. Cyclin C, along with its cyclin dependent kinase partner Cdk8, associates with the RNA polymerase holoenzyme to regulate transcription. In particular, cyclin C-Cdk8 repress many stress responsive genes. To relieve this repression, cyclin C is destroyed in cells exposed to pro-oxidants and other stressors. However, prior to its destruction, cyclin C, but not Cdk8, is released from its nuclear anchor (Med13), translocates from the nucleus to the cytoplasm where it interacts with the fission machinery and is both necessary and sufficient to induce extensive mitochondria fragmentation. Furthermore, cytoplasmic cyclin C promotes PCD indicating that it mediates both mitochondrial fission and cell death pathways. This review will summarize the role cyclin C plays in regulating stress-responsive transcription. In addition, we will detail this new function mediating mitochondrial fission and PCD. Although both these roles of cyclin C are conserved, this review will concentrate on cyclin C's dual role in the budding yeast Saccharomyces cerevisiae.
Highlights
ROLE 1: Cyclin C IS A TRANSCRIPTION FACTOR REPRESSING STRESS-RESPONSIVE GENES Cyclin C-Cdk8 kinase is a part of the Mediator complex The cyclin protein family was initially identified as promoters of cell cycle progression by binding and activating cyclin dependent kinases (Cdks)
Recruitment of cyclin C-Cdk8 to promoters occurs through the Mediator, a large complex that plays a central role in modulating RNA polymerase II activity [12, 13]
In addition to stimulating transcription factors involved in stress gene induction, the cell wall integrity (CWI) pathway is responsible for mediating cyclin C destruction
Summary
ROLE 1: Cyclin C IS A TRANSCRIPTION FACTOR REPRESSING STRESS-RESPONSIVE GENES Cyclin C-Cdk8 kinase is a part of the Mediator complex The cyclin protein family was initially identified as promoters of cell cycle progression by binding and activating cyclin dependent kinases (Cdks). Recruitment of cyclin C-Cdk8 to promoters occurs through the Mediator, a large complex that plays a central role in modulating RNA polymerase II activity [12, 13] (and reviewed in [14]). The cyclin C-Cdk8 kinase primarily represses transcription of genes responding to environmental cues Potential targets of cyclin C-Cdk8 that affect transcriptional control include other mediator components, transcription factors, chromatin and the RNA polymerase II itself (see [19] for review).
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