The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer

Vervoort, Stephin J.; Welsh, Sarah A.; Devlin, Jennifer R.; Barbieri, Elisa; Knight, Deborah; Offley, Sarah; Bjelosevic, Stefan; Costacurta, Matteo; Todorovski, Izabela; Kearney, Conor J.; Sandow, Jarrod J.; Fan, Zheng; Blyth, Benjamin J.; McLeod, Victoria M.; Vissers, Jmh Jan; Pavic, Karolina; Martin, Ben P.; Gregory, Gareth P.; Demosthenous, Elena; Zethoven, Magnus; Kong, Isabella Y.; Hawkins, Edwin D.; Hogg, Simon J.; Kelly, Madison J.; Newbold, Andrea; Simpson, Kaylene J.; Kauko, Otto; Harvey, Ken; Ohlmeyer, Michael; Westermarck, Jukka; Gray, Nathanael S.; Gardini, Alessandro; Johnstone, Ricky W.

doi:10.1016/j.cell.2021.04.022

Cited by 138 publications

(158 citation statements)

References 117 publications

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“…Although this association might influence PP2A stability, an alternative and exciting possibility is that PBAF recruits PP2A to regulate transcription at target loci. Evidence for a transcriptional role was recently reported in human and Drosophila cell lines, where PP2A regulates transcriptional pausing 69 .…”

Section: Discussionmentioning

confidence: 87%

Mammalian SWI/SNF chromatin remodeler is essential for reductional meiosis in males

et al. 2021

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The mammalian SWI/SNF nucleosome remodeler is essential for spermatogenesis. Here, we identify a role for ARID2, a PBAF (Polybromo - Brg1 Associated Factor)-specific subunit, in meiotic division. Arid2cKO spermatocytes arrest at metaphase-I and are deficient in spindle assembly, kinetochore-associated Polo-like kinase1 (PLK1), and centromeric targeting of Histone H3 threonine3 phosphorylation (H3T3P) and Histone H2A threonine120 phosphorylation (H2AT120P). By determining ARID2 and BRG1 genomic associations, we show that PBAF localizes to centromeres and promoters of genes known to govern spindle assembly and nuclear division in spermatocytes. Consistent with gene ontology of target genes, we also identify a role for ARID2 in centrosome stability. Additionally, misexpression of genes such as Aurkc and Ppp1cc (Pp1γ), known to govern chromosome segregation, potentially compromises the function of the chromosome passenger complex (CPC) and deposition of H3T3P, respectively. Our data support a model where-in PBAF activates genes essential for meiotic cell division.

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Section: Discussionmentioning

confidence: 87%

Mammalian SWI/SNF chromatin remodeler is essential for reductional meiosis in males

et al. 2021

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“…We have recently found that Integrator associates with protein phosphatase 2A core enzyme (PP2A-AC) and dephosphorylates the C-terminal domain (CTD) of Pol II and determined the structure of Integrator-containing PP2A-AC (termed INTAC), showing how the RNA nuclease and protein phosphatase are organized in the INTAC complex 7 . In addition, Integrator-bound PP2A dephosphorylates Pol II CTD and Spt5 to prevent the transition to productive elongation 7,24,29 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis of INTAC-regulated transcription

Zheng

Jin

et al. 2021

Preprint

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For the majority of expressed eukaryotic genes, RNA polymerase II (Pol II) forms a paused elongation complex (PEC) and undergoes promoter-proximal pausing downstream of the transcription start site 1–3. The polymerase either proceeds into productive elongation or undergoes promoter-proximal premature transcription termination 4–6. It remains incompletely understood how transcription is regulated at this stage. Here, we determined the structure of PEC bound to INTAC, an Integrator-containing PP2A complex 7, at near-atomic resolution. The structure shows that INTAC partially wraps around PEC through multiple contacts, permitting the memetic nascent RNA to run into substrate-entry tunnel of the endonuclease subunit INTS11 of INTAC for cleavage. Pol II C-terminal domain (CTD) winds over INTAC backbone module through multiple anchors and is suspended above the phosphatase of INTAC for dephosphorylation. Biochemical analysis shows that INTAC-PEC association requires unphosphorylated CTD and could tolerate CTD phosphorylation, suggesting an INTAC-mediated persistent CTD dephosphorylation followed by reinforcement of the INTAC-PEC complex. Our study reveals how INTAC binds PEC and orchestrates RNA cleavage and CTD dephosphorylation, two critical events in generating premature transcription termination.

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“…Multiple types of solid and hematopoietic malignancies are addicted to elevated transcription rates and are, therefore, sensitive to CDK9 inhibitors ( 138–140 ). It was recently discovered that the INTAC complex directly opposes CDK9 phosphorylation and that treatment with a small molecule activator of PP2A (SMAP) synergizes with CDK9 inhibition ( 132 ). In addition, SPT5, an essential positive regulator of transcription and a target of CDK9 phosphorylation, has also been observed to be negatively regulated by the INTAC complex, further supporting CDK9 inhibitor/PP2A activator synergy (Figure 3 ) ( 133 , 141 ).…”

Section: Interplay Of Pp2a and Chromatin Remodeling Complexesmentioning

confidence: 99%

PP2A and cancer epigenetics: a therapeutic opportunity waiting to happen

Tinsley

Allen-Petersen

2022

NAR Cancer

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The epigenetic state of chromatin is altered by regulators which influence gene expression in response to environmental stimuli. While several post-translational modifications contribute to chromatin accessibility and transcriptional programs, our understanding of the role that specific phosphorylation sites play is limited. In cancer, kinases and phosphatases are commonly deregulated resulting in increased oncogenic signaling and loss of epigenetic regulation. Aberrant epigenetic states are known to promote cellular plasticity and the development of therapeutic resistance in many cancer types, highlighting the importance of these mechanisms to cancer cell phenotypes. Protein Phosphatase 2A (PP2A) is a heterotrimeric holoenzyme that targets a diverse array of cellular proteins. The composition of the PP2A complex influences its cellular targets and activity. For this reason, PP2A can be tumor suppressive or oncogenic depending on cellular context. Understanding the nuances of PP2A regulation and its effect on epigenetic alterations can lead to new therapeutic avenues that afford more specificity and contribute to the growth of personalized medicine in the oncology field. In this review, we summarize the known PP2A-regulated substrates and potential phosphorylation sites that contribute to cancer cell epigenetics and possible strategies to therapeutically leverage this phosphatase to suppress tumor growth.

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The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer

Cited by 138 publications

References 117 publications

Mammalian SWI/SNF chromatin remodeler is essential for reductional meiosis in males

Mammalian SWI/SNF chromatin remodeler is essential for reductional meiosis in males

Structural basis of INTAC-regulated transcription

PP2A and cancer epigenetics: a therapeutic opportunity waiting to happen

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