Pierre Chymkowitch

Nothnagel PMC, Meslin P-A, Wik JA , Strøm YE, Bjørås M, Enserink JM, Skålhegg BS, Briand N, Mathelier A and Chymkowitch P (2026). Transient SUMOylation Inhibition In Human Pre-adipocytes Stably Imprints a Transcriptional Beiging Fate. Nucleic Acids Res. Mar 19;54(6):gkag232.

Bjune JI, Laber S, Lawrence-Archer L, Nothnagel PMC, Zhao X, Yamada S, Al-Sharabi N, Mustafa K, Njølstad PR, Claussnitzer M, Cox RD, Chymkowitch P, Mellgren G and Dankel SN (2025). IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells. Nature Communications Aug 6;16(1):7248

Dufour D, Zhao X, Chaleil F, Nothnagel PMC, Bjørås M, Lefrancois-Martinez A-M, Martinez A and Chymkowitch P (2025). Pharmacological Inhibition of SUMOylation with TAK-981 Mimics Genetic HypoSUMOylation in Murine Perigonadal White Adipose Tissue. Adipocyte Dec;14(1):2474107

Ramos-Alonso L, Holland P, Le Gras S, Zhao X, Jost B, Bjørås M, Barral Y, Enserink JM and Chymkowitch P (2023). Mitotic chromosome condensation resets chromatin to maintain transcriptional homeostasis. Proc Natl Acad Sci U S A  Jan 24;120(4):e2210593120

Zhao X, Hendriks IA, Le Gras S, Ye T, Nguéa P A, Ramos-Alonso L, Flor Lien G, Klungland A, Jost B, Enserink JM, Nilsen ML and Chymkowitch P (2022). Waves of sumoylation support transcription dynamics during adipocyte differentiation. Nucleic Acids Res. Feb 22;50(3):1351-1369.

Garcia I, Munoz S, Ramos-Alonso L, Andersen AN, Zimmermann C, Erikson J, Bøe SO, Kaferle P, Papamichos-Chronakis M, Chymkowitch P, Enserink JM (2021). Kel1 is a phosphorylation-regulated noise suppressor of the pheromone signaling pathway. Cell Reports 37, 110186, December 28

Nguéa P A, Robertson J, Herrera MC, Chymkowitch P, Enserink JM (2019). De-sumoylation of RNAPIII Lies at the Core of the Sumo-Stress Response in yeast. J. Biol. Chem. Dec 06; 294: 18784 

Kruitwagen T*, Chymkowitch P*, Denoth-Lippuner A, Enserink JM, Barral Y (2018). Centromeres license the mitotic condensation of yeast chromosome arms. Cell  Oct 18;175(3):780-795.e15

Chymkowitch P, Nguéa P A, Aanes H, Robertson J, Klungland A, Enserink JM (2017). TORC1-dependent sumoylation of Rpc82 promotes RNA polymerase III assembly and activity. Proc Natl Acad Sci U S A Jan 31;114(5):1039-1044

Chymkowitch P, Nguéa P A, Aanes H, Koehler CJ, Thiede B, Lorenz S, Meza-Zepeda LA, Klungland A, Enserink JM (2015). Sumoylation of Rap1 Mediates the Recruitment of TFIID to Promote Transcription of Ribosomal Protein Genes. Genome Res. Jun;25(6):897-906

Chymkowitch P, Eldholm V, Lorenz S, Zimmermann C, Lindvall JM, Bjørås M, Meza-Zepeda LA, Enserink JM (2012). Cdc28 kinase activity regulates the basal transcription machinery at a subset of genes. Proc Natl Acad Sci U S A Jun 26;109(26):10450-5

Chymkowitch P, Le May N, Charneau P, Compe E, Egly JM (2011). The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process. EMBO J. Feb 2;30(3):468-79

Ito S, Kuraoka I, Chymkowitch P, Compe E, Takedachi A, Ishigami C, Coin F, Egly JM, Tanaka K (2007). XPG stabilizes TFIIH, allowing transactivation of nuclear receptors: Implications for Cokayne syndrome in XP-G/CS patients. Mol. Cell Apr 27;26(2):231-43

• Nothnagel, Patrizia Maria Christiane; Meslin, Paul-Arthur Richard; Wik, Jonas Aakre; Dufour, Damien; Strøm, Yunna Erika & Bjørås, Magnar [Show all 11 contributors for this article] (2026). Transient SUMOylation inhibition in human pre-adipocytes stably imprints a transcriptional beiging fate. Nucleic Acids Research (NAR). ISSN 0305-1048. 54(6), p. 1–22. doi: 10.1093/nar/gkag232. Full text in Research Archive Show summary

  SUMOylation regulates chromatin states and transcriptional programs that preserve cellular identity, yet how perturbation of the SUMOylation pathway impacts adipocyte plasticity remains unclear. Here, we show that brief pharmacologic inhibition of SUMOylation in human pre-adipocytes using TAK-981 primes stable de novo beige differentiation in the presence of the PPARG agonist rosiglitazone. Transient TAK-981 exposure produces changes in the transcriptome and metabolism of mature adipocytes, including robust induction of canonical beiging markers like UCP1 and increased mitochondrial respiration. Mechanistically, ATAC-seq and RNA-sequencing revealed immediate chromatin remodeling and early mobilization of CEBP family members, followed by stable activation of CEBPA and PPARG regulatory networks. ChIP experiments demonstrated loss of H3K27me3 and gain of H3K27ac at PPAR response elements at thermogenic enhancers, and increased PPARG occupancy across the UCP1 regulatory unit. This mechanism is enforced by enhanced cAMP-PKA-p38 signaling and stabilization of beiging transcription activators. We propose that transient relief of SUMO-mediated repression unlocks dominant regulatory units, notably the UCP1 enhancer cluster, producing a monomorphic reprogramming toward adaptive thermogenesis. These findings identify SUMOylation as a reversible epigenetic barrier to adipocyte beiging and suggest that temporally controlled SUMO pathway inhibition combined with PPARG activation could be exploited to modulate adipose tissue thermogenic capacity.

• Nothnagel, Patrizia Maria Christiane; Meslin, Paul-Arthur Richard; Wik, Jonas Aakre; Strøm, Yunna Erika; Bjørås, Magnar & Enserink, Jorrit [Show all 10 contributors for this article] (2025). Transient SUMOylation Inhibition In Human Pre-adipocytes Stably Imprints a Transcriptional Beiging Fate. bioRxiv (preprint article). 54(6). doi: 10.1101/2025.03.07.642034. Full text in Research Archive Show summary

  Abstract SUMOylation regulates chromatin states and transcriptional programs that preserve cellular identity, yet how transient perturbation of the SUMO pathway impacts adipocyte plasticity remains unclear. Here we show that brief pharmacologic inhibition of SUMO conjugation in human pre-adipocytes using TAK-981 primes stable de novo beige differentiation in the presence of the PPARG agonist rosiglitazone. Transient TAK-981 exposure before adipogenic induction produces long-lasting changes in the transcriptome and metabolism of mature adipocytes, including robust induction of canonical beiging markers like UCP1 and increased mitochondrial respiration. Mechanistically, ATAC-seq and transcription factor footprinting revealed immediate and durable chromatin remodeling and early mobilization of CEBP family members, followed by stable activation of CEBPA and PPARG regulatory networks. ChIP experiments demonstrated loss of H3K27me3 and gain of H3K27ac at PPAR response elements within key thermogenic enhancers, with increased PPARG occupancy across the UCP1 regulatory unit. This mechanism is enforced by enhanced cAMP-PKA-p38 signaling, and stabilization of beiging transcriptional activators. Our data support a model in which transient relief of SUMO-mediated repression unlocks dominant regulatory units, notably the UCP1 enhancer cluster, producing a monomorphic, cell type specific reprogramming toward adaptive thermogenesis. These findings identify SUMOylation as a reversible epigenetic barrier to adipocyte beiging and suggest that temporally controlled SUMO pathway inhibition combined with PPARG activation could be exploited to modulate adipose tissue thermogenic capacity. Graphical abstract SUMOylation restricts de novo differentiation of pre-adipocytes into beige adipocytes by repressing cAMP signaling and preventing epigenetic and transcriptional reprogramming of white adipocytes.

• Dufour, Damien; Zhao, Xu; Chaleil, Florian; Nothnagel, Patrizia Maria Christiane; Bjørås, Magnar & Lefrançois-Martinez, Anne-Marie [Show all 8 contributors for this article] (2025). Pharmacological inhibition of SUMOylation with TAK-981 mimics genetic HypoSUMOylation in murine perigonadal white adipose tissue. Adipocyte. ISSN 2162-3945. 14(1). doi: 10.1080/21623945.2025.2474107. Full text in Research Archive Show summary

  Post-translational modification by the small ubiquitin-like modifier (SUMO) is essential for cellular differentiation and homeostasis. Here, we investigate the role of SUMOylation in adipose tissue development using TAK-981, a pharmacological inhibitor of SUMOylation. Administration of TAK-981 to mice resulted in significant defect in weight gain and adipocyte atrophy in perigonadal white adipose tissue (gWAT) depots. Gene expression analyses revealed a marked downregulation of adipogenic genes, including Pparg, Cebpa, and Fasn. Our data thus indicate that TAK-981 treatment impaired adipogenesis in gWAT, consistent with prior findings that SUMOylation supports transcriptional regulation of adipogenesis and lipid metabolism. We also found significant infiltration of immune cells and efferocytosis in gWAT. Our results thus indicate that SUMOylation inhibition using a small molecule phenocopies genetic hypoSUMOylation models, highlighting its critical role in maintaining adipocyte functionality and immune environment. These findings provide evidence that SUMOylation is essential for fat accumulation in vivo. Furthermore, given that TAK-981 is currently under clinical evaluation for the treatment of solid tumors, our results underscore the importance of considering the potential unintended effects of SUMOylation inhibition on adipose tissue in patients.

• Bjune, Jan-Inge; Laber, Samantha; Dyer, Laurence; Nothnagel, Patrizia Maria Christiane; Yamada, Shuntaro & Zhao, Xu [Show all 15 contributors for this article] (2025). IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells. Nature Communications. 16. doi: 10.1038/s41467-025-62361-1. Full text in Research Archive Show summary

  IRX3 is linked to predisposition to obesity through the FTO locus and is upregulated during early adipogenesis in risk-allele carriers, shifting adipocyte fate toward fat storage. However, how this elevated IRX3 expression influences later developmental stages remains unclear. Here we show that IRX3 regulates adipocyte fate by modulating epigenetic reprogramming. ChIP-sequencing in preadipocytes identifies over 300 IRX3 binding sites, predominantly at promoters of genes involved in SUMOylation and chromatin remodeling. IRX3 knockout alters expression of SUMO pathway genes, increases global SUMOylation, and inhibits PPARγ activity and adipogenesis. Pharmacological SUMOylation inhibition rescues these effects. IRX3 KO also reduces SUMO occupancy at Wnt-related genes, enhancing Wnt signaling and promoting osteogenic fate in 3D cultures. This fate switch is partially reversible by SUMOylation inhibition. We identify IRX3 as a key transcriptional regulator of epigenetic programs, acting upstream of SUMOylation to maintain mesenchymal identity and support adipogenesis while suppressing osteogenesis in mouse embryonic fibroblasts.

• Corrales, Jeanne Gaspar; Alonso, Lucia Ramos; González-Sabín, Javier; Ríos-Lombardía, Nicolás; Trevijano-Contador, Nuria & Berg, Henriette Engen [Show all 12 contributors for this article] (2024). Characterization of a selective, iron-chelating antifungal compound that disrupts fungal metabolism and synergizes with fluconazole. Microbiology spectrum. 12(2). doi: 10.1128/spectrum.02594-23. Full text in Research Archive Show summary

  Fungal infections are a growing global health concern due to the limited number of available antifungal therapies as well as the emergence of fungi that are resistant to first-line antimicrobials, particularly azoles and echinocandins. Development of novel, selective antifungal therapies is challenging due to similarities between fungal and mammalian cells. An attractive source of potential antifungal treatments is provided by ecological niches co-inhabited by bacteria, fungi, and multicellular organisms, where complex relationships between multiple organisms have resulted in evolution of a wide variety of selective antimicrobials. Here, we characterized several analogs of one such natural compound, collismycin A. We show that NR-6226C has antifungal activity against several pathogenic Candida species, including C. albicans and C. glabrata, whereas it only has little toxicity against mammalian cells. Mechanistically, NR-6226C selectively chelates iron, which is a limiting factor for pathogenic fungi during infection. As a result, NR-6226C treatment causes severe mitochondrial dysfunction, leading to formation of reactive oxygen species, metabolic reprogramming, and a severe reduction in ATP levels. Using an in vivo model for fungal infections, we show that NR-6226C significantly increases survival of Candida-infected Galleria mellonella larvae. Finally, our data indicate that NR-6226C synergizes strongly with fluconazole in inhibition of C. albicans. Taken together, NR-6226C is a promising antifungal compound that acts by chelating iron and disrupting mitochondrial functions.

• Alonso, Lucia Ramos; Holland, Petter; Gras, Stéphanie Le; Zhao, Xu; Jost, Bernard & Bjørås, Magnar [Show all 9 contributors for this article] (2023). Mitotic chromosome condensation resets chromatin to safeguard transcriptional homeostasis during interphase. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 120(4). doi: 10.1073/pnas.2210593120. Full text in Research Archive Show summary

  Mitotic entry correlates with the condensation of the chromosomes, changes in histone modifications, exclusion of transcription factors from DNA, and the broad downregulation of transcription. However, whether mitotic condensation influences transcription in the subsequent interphase is unknown. Here, we show that preventing one chromosome to condense during mitosis causes it to fail resetting of transcription. Rather, in the following interphase, the affected chromosome contains unusually high levels of the transcription machinery, resulting in abnormally high expression levels of genes in cis, including various transcription factors. This subsequently causes the activation of inducible transcriptional programs in trans, such as the GAL genes, even in the absence of the relevant stimuli. Thus, mitotic chromosome condensation exerts stringent control on interphase gene expression to ensure the maintenance of basic cellular functions and cell identity across cell divisions. Together, our study identifies the maintenance of transcriptional homeostasis during interphase as an unexpected function of mitosis and mitotic chromosome condensation.

• Alonso, Lucia Ramos & Chymkowitch, Pierre (2023). Maintaining transcriptional homeostasis during cell cycle. Transcription. ISSN 2154-1264. doi: 10.1080/21541264.2023.2246868. Full text in Research Archive Show summary

  The preservation of gene expression patterns that define cellular identity throughout the cell division cycle is essential to perpetuate cellular lineages. However, the progression of cells through different phases of the cell cycle severely disrupts chromatin accessibility, epigenetic marks, and the recruitment of transcriptional regulators. Notably, chromatin is transiently disassembled during S-phase and undergoes drastic condensation during mitosis, which is a significant challenge to the preservation of gene expression patterns between cell generations. This article delves into the specific gene expression and chromatin regulatory mechanisms that facilitate the preservation of transcriptional identity during replication and mitosis. Furthermore, we emphasize our recent findings revealing the unconventional role of yeast centromeres and mitotic chromosomes in maintaining transcriptional fidelity beyond mitosis.

• Zhao, Xu; Hendriks, Ivo A; Gras, Stephanie Le; Ye, Tao; Alonso, Lucia Ramos & P, Aurélie Nguéa [Show all 13 contributors for this article] (2022). Waves of sumoylation support transcription dynamics during adipocyte differentiation. Nucleic Acids Research (NAR). ISSN 0305-1048. 50(3), p. 1351–1369. doi: 10.1093/nar/gkac027. Full text in Research Archive Show summary

  Abstract Tight control of gene expression networks required for adipose tissue formation and plasticity is essential for adaptation to energy needs and environmental cues. However, the mechanisms that orchestrate the global and dramatic transcriptional changes leading to adipocyte differentiation remain to be fully unraveled. We investigated the regulation of nascent transcription by the sumoylation pathway during adipocyte differentiation using SLAMseq and ChIPseq. We discovered that the sumoylation pathway has a dual function in differentiation; it supports the initial downregulation of pre-adipocyte-specific genes, while it promotes the establishment of the mature adipocyte transcriptional program. By characterizing endogenous sumoylome dynamics in differentiating adipocytes by mass spectrometry, we found that sumoylation of specific transcription factors like PPARγ/RXR and their co-factors are associated with the transcription of adipogenic genes. Finally, using RXR as a model, we found that sumoylation may regulate adipogenic transcription by supporting the chromatin occurrence of transcription factors. Our data demonstrate that the sumoylation pathway supports the rewiring of transcriptional networks required for formation of functional adipocytes. This study also provides the scientists in the field of cellular differentiation and development with an in-depth resource of the dynamics of the SUMO-chromatin landscape, SUMO-regulated transcription and endogenous sumoylation sites during adipocyte differentiation.

• Enserink, Jorrit & Chymkowitch, Pierre (2022). Cell Cycle-Dependent Transcription: The Cyclin Dependent Kinase Cdk1 Is a Direct Regulator of Basal Transcription Machineries. International Journal of Molecular Sciences. ISSN 1661-6596. 23(3), p. 1–23. doi: 10.3390/ijms23031293. Full text in Research Archive Show summary

  The cyclin-dependent kinase Cdk1 is best known for its function as master regulator of the cell cycle. It phosphorylates several key proteins to control progression through the different phases of the cell cycle. However, studies conducted several decades ago with mammalian cells revealed that Cdk1 also directly regulates the basal transcription machinery, most notably RNA polymerase II. More recent studies in the budding yeast Saccharomyces cerevisiae have revisited this function of Cdk1 and also revealed that Cdk1 directly controls RNA polymerase III activity. These studies have also provided novel insight into the physiological relevance of this process. For instance, cell cycle-stage-dependent activity of these complexes may be important for meeting the increased demand for various proteins involved in housekeeping, metabolism, and protein synthesis. Recent work also indicates that direct regulation of the RNA polymerase II machinery promotes cell cycle entry. Here, we provide an overview of the regulation of basal transcription by Cdk1, and we hypothesize that the original function of the primordial cell-cycle CDK was to regulate RNAPII and that it later evolved into specialized kinases that govern various aspects of the transcription machinery and the cell cycle.

• Alonso, Lucia Ramos; Llorente, Ignacio Garcia; Enserink, Jorrit & Chymkowitch, Pierre (2022). Analysis of the pheromone signaling pathway by RT-qPCR in the budding yeast Saccharomyces cerevisiae. STAR Protocols. 3(1). doi: 10.1016/j.xpro.2022.101210. Full text in Research Archive Show summary

  FUS3 and STE2 expression levels can be used as reporters for signaling through the pheromone pathway in the budding yeast Saccharomyces cerevisiae. Here, we describe an optimized protocol to measure the expression levels of FUS3 and STE2 using quantitative reverse transcription PCR (RT-qPCR). We describe the steps for comparing untreated and pheromone-treated yeast cells and how to quantify the changes in various deletion strains. The protocol can be applied to determine potential regulators of the pheromone pathway. For complete details on the use and execution of this protocol, please refer to Garcia et al. (2021).

• Llorente, Ignacio Garcia; Munoz, Sara Orellana; Alonso, Lucia Ramos; Andersen, Aram Nikolai; Zimmermann, Christine & Eriksson, Jens [Show all 11 contributors for this article] (2021). Kel1 is a phosphorylation-regulated noise suppressor of the pheromone signaling pathway. Cell reports. 37(13), p. 1–20. doi: 10.1016/j.celrep.2021.110186. Full text in Research Archive Show summary

  Mechanisms have evolved that allow cells to detect signals and generate an appropriate response. The accuracy of these responses relies on the ability of cells to discriminate between signal and noise. How cells filter noise in signaling pathways is not well understood. Here, we analyze noise suppression in the yeast pheromone signaling pathway and show that the poorly characterized protein Kel1 serves as a major noise suppressor and prevents cell death. At the molecular level, Kel1 prevents spontaneous activation of the pheromone response by inhibiting membrane recruitment of Ste5 and Far1. Only a hypophosphorylated form of Kel1 suppresses signaling, reduces noise, and prevents pheromone-associated cell death, and our data indicate that the MAPK Fus3 contributes to Kel1 phosphorylation. Taken together, Kel1 serves as a phospho-regulated suppressor of the pheromone pathway to reduce noise, inhibit spontaneous activation of the pathway, regulate mating efficiency, and prevent pheromone-associated cell death.

• P, Aurélie Nguéa; Robertson, Joseph; Herrera, Maria Carmen; Chymkowitch, Pierre & Enserink, Jorrit (2019). Desumoylation of RNA polymerase III lies at the core of the Sumo stress response in yeast. Journal of Biological Chemistry. ISSN 0021-9258. 294(49), p. 18784–18795. doi: 10.1074/jbc.RA119.009721. Full text in Research Archive Show summary

  Post-translational modification by small ubiquitin-like modifier (Sumo) regulates many cellular processes, including the adaptive response to various types of stress, referred to as the Sumo stress response (SSR). However, it remains unclear whether the SSR involves a common set of core proteins regardless of the type of stress or whether each particular type of stress induces a stress-specific SSR that targets a unique, largely nonoverlapping set of Sumo substrates. In this study, we used MS and a Gene Ontology approach to identify differentially sumoylated proteins during heat stress, hyperosmotic stress, oxidative stress, nitrogen starvation, and DNA alkylation in Saccharomyces cerevisiae cells. Our results indicate that each stress triggers a specific SSR signature centered on proteins involved in transcription, translation, and chromatin regulation. Strikingly, whereas the various stress-specific SSRs were largely nonoverlapping, all types of stress tested here resulted in desumoylation of subunits of RNA polymerase III, which correlated with a decrease in tRNA synthesis. We conclude that desumoylation and subsequent inhibition of RNA polymerase III constitutes the core of all stress-specific SSRs in yeast.

• Chymkowitch, Pierre & Enserink, Jorrit (2018). Regulation of tRNA synthesis by posttranslational modifications of RNA polymerase III subunits. Biochimica et Biophysica Acta. Gene Regulatory Mechanisms. ISSN 1874-9399. 1861(4), p. 310–319. doi: 10.1016/j.bbagrm.2017.11.001. Full text in Research Archive Show summary

  RNA polymerase III (RNAPIII) transcribes tRNA genes, 5S RNA as well as a number of other non-coding RNAs. Because transcription by RNAPIII is an energy-demanding process, its activity is tightly linked to the stress levels and nutrient status of the cell. Multiple signaling pathways control RNAPIII activity in response to environmental cues, but exactly how these pathways regulate RNAPIII is still poorly understood. One major target of these pathways is the transcriptional repressor Maf1, which inhibits RNAPIII activity under conditions that are detrimental to cell growth. However, recent studies have found that the cell can also directly regulate the RNAPIII machinery through phosphorylation and sumoylation of RNAPIII subunits. In this review we summarize post-translational modifications of RNAPIII subunits that mainly have been identified in large-scale proteomics studies, and we highlight several examples to discuss their relevance for regulation of RNAPIII.

• Kruitwagen, Tom; Chymkowitch, Pierre; Denoth-Lippuner, Annina; Enserink, Jorrit & Barral, Yves (2018). Centromeres License the Mitotic Condensation of Yeast Chromosome Arms. Cell. ISSN 0092-8674. 175(3), p. 780–795.e15. doi: 10.1016/j.cell.2018.09.012. Full text in Research Archive Show summary

  During mitosis, chromatin condensation shapes chromosomes as separate, rigid, and compact sister chromatids to facilitate their segregation. Here, we show that, unlike wild-type yeast chromosomes, non-chromosomal DNA circles and chromosomes lacking a centromere fail to condense during mitosis. The centromere promotes chromosome condensation strictly in cis through recruiting the kinases Aurora B and Bub1, which trigger the autonomous condensation of the entire chromosome. Shugoshin and the deacetylase Hst2 facilitated spreading the condensation signal to the chromosome arms. Targeting Aurora B to DNA circles or centromere-ablated chromosomes or releasing Shugoshin from PP2A-dependent inhibition bypassed the centromere requirement for condensation and enhanced the mitotic stability of DNA circles. Our data indicate that yeast cells license the chromosome-autonomous condensation of their chromatin in a centromere-dependent manner, excluding from this process non-centromeric DNA and thereby inhibiting their propagation.

• Herrera, Maria Carmen; Chymkowitch, Pierre; Robertson, Joseph; Eriksson, Jens; Bøe, Stig Ove & Alseth, Ingrun [Show all 7 contributors for this article] (2018). Cdk1 gates cell cycle-dependent tRNA synthesis by regulating RNA polymerase III activity. Nucleic Acids Research (NAR). ISSN 0305-1048. 46(22), p. 11698–11711. doi: 10.1093/nar/gky846. Full text in Research Archive Show summary

  tRNA genes are transcribed by RNA polymerase III (RNAPIII). During recent years it has become clear that RNAPIII activity is strictly regulated by the cell in response to environmental cues and the homeostatic status of the cell. However, the molecular mechanisms that control RNAPIII activity to regulate the amplitude of tDNA transcription in normally cycling cells are not well understood. Here, we show that tRNA levels fluctuate during the cell cycle and reveal an underlying molecular mechanism. The cyclin Clb5 recruits the cyclin dependent kinase Cdk1 to tRNA genes to boost tDNA transcription during late S phase. At tDNA genes, Cdk1 promotes the recruitment of TFIIIC, stimulates the interaction between TFIIIB and TFIIIC, and increases the dynamics of RNA polymerase III in vivo. Furthermore, we identified Bdp1 as a putative Cdk1 substrate in this process. Preventing Bdp1 phosphorylation prevented cell cycle-dependent recruitment of TFIIIC and abolished the cell cycle-dependent increase in tDNA transcription. Our findings demonstrate that under optimal growth conditions Cdk1 gates tRNA synthesis in S phase by regulating the RNAPIII machinery, revealing a direct link between the cell cycle and RNAPIII activity.

• Zimmermann, Christine; Llorente, Ignacio Garcia; Omerzu, Manja; Chymkowitch, Pierre; Zhang, Beibei & Enserink, Jorrit (2017). Mapping the synthetic dosage lethality network of CDK1/CDC28. G3: Genes, Genomes, Genetics. 7(6), p. 1753–1766. doi: 10.1534/g3.117.042317. Full text in Research Archive Show summary

  Cdk1 (Cdc28 in yeast) is a cyclin-dependent kinase (CDK) essential for cell cycle progression and cell division in normal cells. However, CDK activity also underpins proliferation of tumor cells, making it a relevant study subject. While numerous targets and processes regulated by Cdc28 have been identified, the exact functions of Cdc28 are only partially understood. To further explore the functions of Cdc28, we systematically overexpressed ∼4800 genes in wild-type (WT) cells and in cells with artificially reduced Cdc28 activity. This screen identified 366 genes that, when overexpressed, specifically compromised cell viability under conditions of reduced Cdc28 activity. Consistent with the crucial functions of Cdc28 in cell cycle regulation and chromosome metabolism, most of these genes have functions in the cell cycle, DNA replication, and transcription. However, a substantial number of genes control processes not directly associated with the cell cycle, indicating that Cdc28 may also regulate these processes. Finally, because the dataset was enriched for direct Cdc28 targets, the results from this screen will aid in identifying novel targets and process regulated by Cdc28.

• Chymkowitch, Pierre; P, Aurélie Nguéa; Aanes, Håvard; Robertson, Joseph; Klungland, Arne & Enserink, Jorrit (2017). TORC1-dependent sumoylation of Rpc82 promotes RNA polymerase III assembly and activity. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 114(5), p. 1039–1044. doi: 10.1073/pnas.1615093114. Full text in Research Archive
• Chymkowitch, Pierre; P, Aurélie Nguéa & Enserink, Jorrit (2015). SUMO-regulated transcription: Challenging the dogma. Bioessays. ISSN 0265-9247. 37(10), p. 1095–1105. doi: 10.1002/bies.201500065. Full text in Research Archive
• Chymkowitch, Pierre; P, Aurélie Nguéa; Aanes, Håvard; Koehler, Christian; Thiede, Bernd & Lorenz, Susanne [Show all 9 contributors for this article] (2015). Sumoylation of Rap1 mediates the recruitment of TFIID to promote transcription of ribosomal protein genes. Genome Research. ISSN 1088-9051. 25(6), p. 897–906. doi: 10.1101/gr.185793.114. Full text in Research Archive
• Zimmermann, Christine; Santos, Aline; Gable, Kenneth; Epstein, Sharon; Gururaj, Charulatha & Chymkowitch, Pierre [Show all 16 contributors for this article] (2013). TORC1 Inhibits GSK3-Mediated Elo2 Phosphorylation to Regulate Very Long Chain Fatty Acid Synthesis and Autophagy. Cell reports. 5(4), p. 1036–1046. doi: 10.1016/j.celrep.2013.10.024. Full text in Research Archive
• Chymkowitch, Pierre & Enserink, Jorrit (2013). The cell cycle rallies the transcription cycle: Cdc28/Cdk1 is a cell cycle-regulated transcriptional CDK. Transcription. ISSN 2154-1264. 4(1), p. 3–6. doi: 10.4161/trns.22456. Full text in Research Archive
• Chymkowitch, Pierre; Eldholm, Vegard; Lorenz, Susanne; Zimmermann, Christine; Lindvall, Jessica M. & Bjørås, Magnar [Show all 8 contributors for this article] (2012). Cdc28 kinase activity regulates the basal transcription machinery at a subset of genes. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 109(26), p. 10450–10455. doi: 10.1073/pnas.1200067109. Full text in Research Archive
• Zimmermann, Christine; Chymkowitch, Pierre; Eldholm, Vegard; Putnam, Christopher D.; Lindvall, Jessica Margareta & Omerzu, Manja [Show all 9 contributors for this article] (2011). A chemical-genetic screen to unravel the genetic network of CDC28/CDK1 links ubiquitin and Rad6-Bre1 to cell cycle progression. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 108(46), p. 18748–18753. doi: 10.1073/pnas.1115885108. Full text in Research Archive

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• Bjune, Jan-Inge; Laber, Samantha; Dyer, Laurence; Xu, Zhao; Claussnitzer, Melina & Njølstad, Pål Rasmus [Show all 11 contributors for this article] (2021). Epigenetic control of adipogenesis by Irx3. Full text in Research Archive
• Zimmermann, Christine; Chymkowitch, Pierre; Eldholm, Vegard; Putnam, Christopher D.; Lindvall, Jessica M. & Omerzu, Manja [Show all 9 contributors for this article] (2012). A chemical-genetic screen to unravel the genetic network of CDC28/CDK1 links ubiquitin and Rad6-Bre1 to cell cycle progression. The FASEB Journal. ISSN 0892-6638. 26. Full text in Research Archive

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