Yin and yang of mediator function revealed by human mutants

Berk, Arnold

doi:10.1073/pnas.1217267109

Cited by 10 publications

(5 citation statements)

References 20 publications

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“…Dysfunction of the transcription machinery components, including Mediator, has been shown to elicit a range of effects on cell states giving rise to diverse disorders including developmental delay and intellectual disability. Variants in Mediator subunits are associated with a wide range of genetic disorders, most of them exhibiting neurological disabilities 4 . Genetic and biochemical studies have established the Mediator Kinase module as a major ingress of developmental and oncogenic signaling through the three other modules constituting the core component, and much of its function derives from its resident CDK8 kinase activity likely regulated by its association with MED13, MED12 and Cyclin C (CycC) subunits.…”

Section: Introductionmentioning

confidence: 99%

Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect

Nizon

Laugel

Flanigan

et al. 2019

Genetics in Medicine

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Purpose-Mediator is a multiprotein complex that allows the transfer of genetic information from DNA binding proteins to the RNA polymerase II during transcription initiation. MED12L is a subunit of the kinase module, which is one of the four sub-complexes of the mediator complex. Other subunits of the kinase module have been already implicated in intellectual disability, namely MED12, MED13L, MED13 and CDK19. Methods-We describe an international cohort of seven affected individuals harboring variants involving MED12L identified by array CGH, exome or genome sequencing. Results-All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment. Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality and mild facial morphological features. Three individuals had a MED12L deletion or duplication. The other four individuals harbored single nucleotide variants (one nonsense, one frameshift and two splicing variants). Functional analysis confirmed a moderate and significant alteration of RNA synthesis in two individuals. Conclusion-Overall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect. Our findings confirm that the integrity of this kinase module is a critical factor for neurological development.

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Section: Introductionmentioning

confidence: 99%

Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect

Nizon

Laugel

Flanigan

et al. 2019

Genetics in Medicine

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“…These coactivators include the Mediator complex, P300 and general transcription factors (Juven-Gershon and Kadonaga, 2010; Malik and Roeder, 2010; Sikorski and Buratowski, 2009; Taatjes, 2010). Recent studies have highlighted the importance of Mediator in integrating information from transcriptional activators, repressors, signaling pathways and other regulators during transcription initiation and during the switch to elongation (Berk, 2012; Borggrefe and Yue, 2011; Conaway and Conaway, 2011; Kagey et al, 2010; Kornberg, 2005; Lariviere et al, 2012; Malik and Roeder, 2010; Spaeth et al, 2011; Taatjes, 2010). …”

Section: Transcriptional Control Of Genesmentioning

confidence: 99%

Transcriptional Regulation and Its Misregulation in Disease

Lee

Young

2013

Cell

1,345

1,076

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The gene expression programs that establish and maintain specific cell states in humans are controlled by thousands of transcription factors, cofactors and chromatin regulators. Misregulation of these gene expression programs can cause a broad range of diseases. Here we review recent advances in our understanding of transcriptional regulation and discuss how these have provided new insights into transcriptional misregulation in disease.

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“…At the mechanistic level, how the CKM executes these different roles is unclear, but likely dependent on specific promoter contexts [ 24 , 25 ]. Deciphering the contribution of the CKM to diverse biological outputs is important as the dysfunction of any of its members is linked to a multitude of human disease, including cancer [ 26 ]. Moreover, in mammalian cells, the kinase module can also encompass the paralogs CDK19, MED12L, and MED13L [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Cdk8 Kinase Module: A Mediator of Life and Death Decisions in Times of Stress

Friedson

Cooper

2021

Microorganisms

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The Cdk8 kinase module (CKM) of the multi-subunit mediator complex plays an essential role in cell fate decisions in response to different environmental cues. In the budding yeast S. cerevisiae, the CKM consists of four conserved subunits (cyclin C and its cognate cyclin-dependent kinase Cdk8, Med13, and Med12) and predominantly negatively regulates a subset of stress responsive genes (SRG’s). Derepression of these SRG’s is accomplished by disassociating the CKM from the mediator, thus allowing RNA polymerase II-directed transcription. In response to cell death stimuli, cyclin C translocates to the mitochondria where it induces mitochondrial hyper-fission and promotes regulated cell death (RCD). The nuclear release of cyclin C requires Med13 destruction by the ubiquitin-proteasome system (UPS). In contrast, to protect the cell from RCD following SRG induction induced by nutrient deprivation, cyclin C is rapidly destroyed by the UPS before it reaches the cytoplasm. This enables a survival response by two mechanisms: increased ATP production by retaining reticular mitochondrial morphology and relieving CKM-mediated repression on autophagy genes. Intriguingly, nitrogen starvation also stimulates Med13 destruction but through a different mechanism. Rather than destruction via the UPS, Med13 proteolysis occurs in the vacuole (yeast lysosome) via a newly identified Snx4-assisted autophagy pathway. Taken together, these findings reveal that the CKM regulates cell fate decisions by both transcriptional and non-transcriptional mechanisms, placing it at a convergence point between cell death and cell survival pathways.

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Yin and yang of mediator function revealed by human mutants

Cited by 10 publications

References 20 publications

Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect

Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect

Transcriptional Regulation and Its Misregulation in Disease

Cdk8 Kinase Module: A Mediator of Life and Death Decisions in Times of Stress

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