scholarly journals CDK12: an emerging therapeutic target for cancer

2018 ◽  
Vol 71 (11) ◽  
pp. 957-962 ◽  
Author(s):  
Goldie Y L Lui ◽  
Carla Grandori ◽  
Christopher J Kemp
Keyword(s):  
Rna Polymerase Ii ◽  
Therapeutic Target ◽  
Cell Function ◽  
Human Cancer ◽  
Cyclin Dependent Kinase ◽  
Cellular Functions ◽  
Synthetic Lethal ◽  
Pancreatic Cancers ◽  
Expression Of Genes ◽  
Synthetic Lethal Interactions

Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases that regulate transcriptional and post-transcriptional processes, thereby modulating multiple cellular functions. Early studies characterised CDK12 as a transcriptional CDK that complexes with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II. CDK12 has been demonstrated to specifically upregulate the expression of genes involved in response to DNA damage, stress and heat shock. More recent studies have implicated CDK12 in regulating mRNA splicing, 3’ end processing, pre-replication complex assembly and genomic stability during embryonic development. Genomic alterations in CDK12 have been detected in oesophageal, stomach, breast, endometrial, uterine, ovarian, bladder, colorectal and pancreatic cancers, ranging from 5% to 15% of sequenced cases. An increasing number of studies point to CDK12 inhibition as an effective strategy to inhibit tumour growth, and synthetic lethal interactions have been described with MYC, EWS/FLI and PARP/CHK1 inhibition. Herein, we discuss the present literature on CDK12 in cell function and human cancer, highlighting important roles for CDK12 as a clinical biomarker for treatment response and potential as an effective therapeutic target.

scholarly journals Effects of Low-Shear Modeled Microgravity on Cell Function, Gene Expression, and Phenotype in Saccharomyces cerevisiae

2006 ◽  
Vol 72 (7) ◽  
pp. 4569-4575 ◽  
Author(s):  
B. Purevdorj-Gage ◽  
K. B. Sheehan ◽  
L. E. Hyman
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Cell Function ◽  
Yeast Cells ◽  
Lag Phase ◽  
Limited Information ◽  
Cellular Functions ◽  
Modeled Microgravity ◽  
Expression Of Genes ◽  
Low Shear

ABSTRACT Only limited information is available concerning the effects of low-shear modeled microgravity (LSMMG) on cell function and morphology. We examined the behavior of Saccharomyces cerevisiae grown in a high-aspect-ratio vessel, which simulates the low-shear and microgravity conditions encountered in spaceflight. With the exception of a shortened lag phase (90 min less than controls; P < 0.05), yeast cells grown under LSMMG conditions did not differ in growth rate, size, shape, or viability from the controls but did differ in the establishment of polarity as exhibited by aberrant (random) budding compared to the usual bipolar pattern of controls. The aberrant budding was accompanied by an increased tendency of cells to clump, as indicated by aggregates containing five or more cells. We also found significant changes (greater than or equal to twofold) in the expression of genes associated with the establishment of polarity (BUD5), bipolar budding (RAX1, RAX2, and BUD25), and cell separation (DSE1, DSE2, and EGT2). Thus, low-shear environments may significantly alter yeast gene expression and phenotype as well as evolutionary conserved cellular functions such as polarization. The results provide a paradigm for understanding polarity-dependent cell responses to microgravity ranging from pathogenesis in fungi to the immune response in mammals.

scholarly journals SETD2 negatively regulates cell size through its catalytic activity and SRI domain

2021 ◽  
Author(s):  
Thom M Molenaar ◽  
Eliza Mari Kwesi-Maliepaard ◽  
Joana Silva ◽  
Muddassir Malik ◽  
William J Faller ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Rna Polymerase Ii ◽  
Cell Size ◽  
Cell Function ◽  
Size Control ◽  
Cell Types ◽  
Negative Regulator ◽  
Cellular Functions ◽  
Global Protein Synthesis

Cell size varies between cell types but is tightly regulated by cell-intrinsic and extrinsic mechanisms. Cell-size control is important for cell function and changes in cell size are frequently observed in cancer cells. Here we uncover a non-canonical role of SETD2 in regulating cell size. SETD2 is a lysine methyltransferase and a tumor suppressor protein involved in transcription regulation, RNA processing and DNA repair. At the molecular level, SETD2 is best known for associating with RNA polymerase II through its Set2-Rbp1 interacting (SRI) domain and methylating histone H3 on lysine 36 (H3K36) during transcription. Although most of the cellular functions of SETD2 have been linked to this activity, several non-histone substrates of SETD2 have recently been identified, some of which have been linked to novel functions of SETD2 beyond chromatin regulation. Using multiple, independent perturbation strategies we identify SETD2 as a negative regulator of global protein synthesis rates and cell size. We provide evidence that this function is dependent on the catalytic activity of SETD2 but independent of H3K36 methylation. Paradoxically, ectopic overexpression of a decoy SRI domain also increased cell size, suggesting that the relevant substrate is engaged by SETD2 via its SRI domain. These data add a central role of SETD2 in regulating cellular physiology and warrant further studies on separating the different functions of SETD2 in cancer development.

scholarly journals A Comparative Genomic Approach for Identifying Synthetic Lethal Interactions in Human Cancer

2013 ◽  
Vol 73 (20) ◽  
pp. 6128-6136 ◽  
Author(s):  
Raamesh Deshpande ◽  
Michael K. Asiedu ◽  
Mitchell Klebig ◽  
Shari Sutor ◽  
Elena Kuzmin ◽  
...  
Keyword(s):  
Human Cancer ◽  
Comparative Genomic ◽  
Synthetic Lethal ◽  
Comparative Genomic Approach ◽  
Genomic Approach ◽  
Synthetic Lethal Interactions

scholarly journals Compromised CDK12 activity causes dependency on the non-essential spliceosome components

2021 ◽  
Author(s):  
Satu Pallasaho ◽  
Aishwarya Gondane ◽  
Damien Duveau ◽  
Craig Thomas ◽  
Massimo Loda ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Treatment Options ◽  
Growth Defect ◽  
Small Scale ◽  
Cyclin Dependent Kinase ◽  
Synthetic Lethal ◽  
Castration Resistant ◽  
Synthetic Lethal Interactions ◽  
Glcnac Transferase ◽  
Mutant Cells

Prostate cancer (PC) is the most common cancer in men and after development of the castration-resistant PC (CRPC), there are no curative treatment options. Inactivating mutations in cyclin-dependent kinase 12 (CDK12) define an aggressive sub-type of CRPC. We hypothesized that compromised CDK12 activity leads to a significant rewiring of the CRPC cells, and that this rewiring results in actionable synthetic lethal interactions. Methods: We used combinatorial lethal screening, ChIP-seq data, RNA-seq data, global alternative splicing analysis, and comprehensive mass spectrometry (MS) profiling to understand how the compromised CDK12 activity rewires the CRPC cells. In addition, we used DepMap-, PC- and CRPC-datasets as a strategy to identify factors that are selectively required by the CDK12-mutant cells. Results: We show that inhibition of O-GlcNAc transferase (OGT) and CDK12 induces cancer cell-selective growth-defect. OGT catalyzes all nucleocytoplasmic O-GlcNAcylation, and we use unbiased MS-profiling to show that the short-term CDK12 inhibition induces hyper-O-GlcNAcylation of the spliceosome-machinery in PC and CRPC cells. Integration of DepMap- and a small scale-drug screen data reveled that depletion of CDK12 activity causes addiction to non-essential spliceosome components (CLK1/4 and SRPK1). CDK12-mutant tumors overexpress CLK1/4 and SRPK1. Finally, we show that the genomes of the CDK12-mutant tumors have lowered DNA methylation, and that CDK12 inhibition induces the expression of the genes marked by DNA methylation. Conclusions: Compromised CDK12 activity rewires DNA methylation, transcription and splicing, and this rewiring renders the affected cells addicted on the non-essential spliceosome components. We propose that inactivation of CDK12 is a biomarker for sensitivity against inhibitors of the non-essential spliceosome components just entering the clinical trials.

scholarly journals Modulation of the Pol II CTD Phosphorylation Code by Rac1 and Cdc42 Small GTPases in Cultured Human Cancer Cells and Its Implication for Developing a Synthetic-Lethal Cancer Therapy

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 621
Author(s):  
Bo Zhang ◽  
Xuelin Zhong ◽  
Moira Sauane ◽  
Yihong Zhao ◽  
Zhi-Liang Zheng
Keyword(s):  
Protein Degradation ◽  
Cancer Cells ◽  
Rna Polymerase Ii ◽  
Rho Gtpases ◽  
Human Cancer ◽  
Small Gtpases ◽  
Pol Ii ◽  
Synthetic Lethal ◽  
Human Cancer Cells ◽  
Cultured Human Cancer Cells

Rho GTPases, including Rho, Cdc42, Rac and ROP subfamilies, are key signaling molecules in RNA polymerase II (Pol II) transcriptional control. Our prior work has shown that plant ROP and yeast Cdc42 GTPases similarly modulate Ser2 and Ser5 phosphorylation status of the C-terminal domain (CTD) of the Pol II largest subunit by regulating CTD phosphatase degradation. Here, we present genetic and pharmacological evidence showing that Cdc42 and Rac1 GTPase signaling modulates a similar CTD Ser2 and Ser5 phosphorylation code in cultured human cancer cells. While siRNA knockdown of Cdc42 and Rac1, respectively, in HeLa cells increased the level of CTD Ser phosphatases RPAP2 and FCP1, they both decreased the level of CTD kinases CDK7 and CDK13. In addition, the protein degradation inhibitor MG132 reversed the effect of THZ1, a CDK7 inhibitor which could decrease the cell number and amount of CDK7 and CDK13, accompanied by a reduction in the level of CTD Ser2 and Ser5 phosphorylation and DOCK4 and DOCK9 (the activators for Rac1 and Cdc42, respectively). Conversely, treatments of Torin1 or serum deprivation, both of which promote protein degradation, could enhance the effect of THZ1, indicating the involvement of protein degradation in controlling CDK7 and CDK13. Our results support an evolutionarily conserved signaling shortcut model linking Rho GTPases to Pol II transcription across three kingdoms, Fungi, Plantae and Animalia, and could lead to the development of a potential synthetic-lethal strategy in controlling cancer cell proliferation or death.

scholarly journals Targeting Cancer at the Intersection of Signaling and Epigenetics

2019 ◽  
Vol 3 (1) ◽  
pp. 365-384
Author(s):  
Stephanie Guerra ◽  
Karen Cichowski
Keyword(s):  
Large Scale ◽  
Human Cancer ◽  
Biological Response ◽  
Specific Drug ◽  
Epigenetic Alterations ◽  
Synthetic Lethal ◽  
Epigenetic State ◽  
Synthetic Lethal Interactions ◽  
A Cell ◽  
Chronic Activation

While mutations resulting in the chronic activation of signaling pathways drive human cancer, the epigenetic state of a cell ultimately dictates the biological response to any given oncogenic signal. Moreover, large-scale genomic sequencing efforts have now identified a plethora of mutations in chromatin regulatory genes in human tumors, which can amplify, modify, or complement traditional oncogenic events. Nevertheless, the co-occurrence of oncogenic and epigenetic defects appears to create novel therapeutic vulnerabilities, which can be targeted by specific drug combinations. Here we discuss general mechanisms by which oncogenic and epigenetic alterations cooperate in human cancer and synthesize the field's early efforts in developing promising therapeutic combinations. Collectively, these studies reveal common themes underlying potential chemical synthetic lethal interactions and support both the expansion and refinement of this type of therapeutic approach.

Synthetic Lethal Interactions Suggest a Role for the Saccharomyces cerevisiae Rtf1 Protein in Transcription Elongation

Genetics ◽  
2000 ◽  
Vol 156 (2) ◽  
pp. 535-547 ◽  
Author(s):  
Patrick J Costa ◽  
Karen M Arndt
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Rna Polymerase Ii ◽  
Transcription Elongation ◽  
Elongation Factor ◽  
Regulation Of Transcription ◽  
Gene Products ◽  
Synthetic Lethal ◽  
Transcription Elongation Factor ◽  
Synthetic Lethal Interactions ◽  
Ctd Phosphatase

Abstract Strong evidence indicates that transcription elongation by RNA polymerase II (pol II) is a highly regulated process. Here we present genetic results that indicate a role for the Saccharomyces cerevisiae Rtf1 protein in transcription elongation. A screen for synthetic lethal mutations was carried out with an rtf1 deletion mutation to identify factors that interact with Rtf1 or regulate the same process as Rtf1. The screen uncovered mutations in SRB5, CTK1, FCP1, and POB3. These genes encode an Srb/mediator component, a CTD kinase, a CTD phosphatase, and a protein involved in the regulation of transcription by chromatin structure, respectively. All of these gene products have been directly or indirectly implicated in transcription elongation, indicating that Rtf1 may also regulate this process. In support of this view, we show that RTF1 functionally interacts with genes that encode known elongation factors, including SPT4, SPT5, SPT16, and PPR2. We also show that a deletion of RTF1 causes sensitivity to 6-azauracil and mycophenolic acid, phenotypes correlated with a transcription elongation defect. Collectively, our results suggest that Rtf1 may function as a novel transcription elongation factor in yeast.

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