A5088653721- RNA modifications and cancer
- RNA Research and Splicing
- Ubiquitin and proteasome pathways
- Glycosylation and Glycoproteins Research
- Cancer-related Molecular Pathways
- Prostate Cancer Treatment and Research
- Invertebrate Immune Response Mechanisms
- RNA and protein synthesis mechanisms
- Carbohydrate Chemistry and Synthesis
- Cancer-related gene regulation
- Cancer Research and Treatments
- Biochemical and Molecular Research
- DNA Repair Mechanisms
- HIV Research and Treatment
- Genomics and Phylogenetic Studies
- interferon and immune responses
- Barrier Structure and Function Studies
- Cancer, Lipids, and Metabolism
- Galectins and Cancer Biology
- RNA regulation and disease
- Complement system in diseases
- Immune Cell Function and Interaction
University of Helsinki
2021-2025
Savitribai Phule Pune University
2019
O-GlcNAcylation of RNA Polymerase II (RNA Pol II) was described in 1993 and here we wanted to probe the functional significance this modification. O-GlcNAc transferase (OGT) is sole enzyme performing nucleo-cytoplasmic O-GlcNAcylation. The role has remained enigmatic partly due lack reagents selectively recognizing O-GlcNAcylated polymerase. We developed a novel approach, wheat germ agglutinin (WGA) lectin-based enrichment for proteins followed by traditional ChIP II, identify...
Abstract Background Phosphorylation and O-GlcNAcylation are the key modifications regulating RNA Polymerase II (RNA Pol II)-driven transcription. Transcriptional kinases, cyclin-dependent kinase 7 (CDK7), CDK9 CDK12 phosphorylate II, whereas is added by O-GlcNAc transferase (OGT) removed O-GlcNAcase (OGA). Currently, no study has systematically evaluated how inhibiting each of these enzyme activities impacts assembly appropriate protein complexes on polymerase maturation mRNA. Methods Here,...
Abstract Cancer cells frequently exhibit hyperactivation of transcription, which can lead to increased sensitivity compounds targeting the transcriptional kinases, in particular CDK9. However, mechanistic details CDK9 inhibition‐induced cancer cell‐selective anti‐proliferative effects remain largely unknown. Here, we discover that inhibition activates innate immune response through viral mimicry cells. In MYC over‐expressing prostate cells, leads gross accumulation mis‐spliced RNA....
Transcription, metabolism and DNA damage response are tightly regulated to preserve the genomic integrity, O-GlcNAc transferase (OGT) is positioned connect three. Prostate cancer most common in men, androgen-ablation therapy halts disease progression. However, a significant number of prostate patients develop resistance against anti-androgens, this incurable termed castration-resistant (CRPC). We have shown that combined inhibition OGT transcription elongation kinase CDK9 induce...
Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes an aggressive sub-group castration-resistant prostate cancer (CRPC). Hyper-activation MYC transcription factor is sufficient to confer the CRPC phenotype. Here, we show that loss CDK12 promotes activity, which renders cells dependent on otherwise non-essential splicing regulatory SRSF protein 1 (SRPK1). High expression associated with increased levels SRPK1 in patient samples, and overexpression sensitizes inhibition using...
Cyclin-dependent kinase 9 (CDK9) phosphorylates RNA polymerase II to promote productive transcription elongation. Here we show that short-term CDK9 inhibition affects the splicing of thousands mRNAs. impairs global and there is no evidence for a coordinated response between alternative overall transcriptome. Alternative feature aggressive prostate cancer (CRPC) enables generation anti-androgen resistant version ligand-independent androgen receptor, AR-v7. We results in loss AR AR-v7...
Abstract Regulation of complement activation in the host cells is mediated primarily by regulators (RCA) family proteins that are formed tandemly repeating control protein (CCP) domains. Functional annotation these proteins, however, challenging as contiguous CCP domains found with varied functions. Here, employing an silico approach, we identify five motifs which conserved spatially a specific order regulatory known RCA proteins. We report presence pattern sufficient to annotate show...
Abstract Co-targeting of O-GlcNAc transferase (OGT) and the transcriptional kinase cyclin-dependent 9 (CDK9) is toxic to prostate cancer cells. As OGT an essential glycosyltransferase, identifying alternative target showing similar effects great interest. Here, we used a multiomics approach (transcriptomics, metabolomics, proteomics) better understand mechanistic basis combinatorial lethality between CDK9 inhibition. inhibition preferentially affected transcription. In contrast, depletion...
O-GlcNAc transferase (OGT) coordinates with regulators of transcription, including cyclin-dependent kinase 12 (CDK12), the major transcription elongation kinase. Here, we use inhibitor- and knockdown-based strategies to show that co-targeting OGT CDK12 is toxic prostate cancer cells. catalyzes all nucleocytoplasmic O-GlcNAcylation due its essentiality in higher eukaryotes, it not an ideal drug target. Our glycoproteomics-data revealed short-term inhibition induces hyper-O-GlcNAcylation...
Abstract Purpose Prostate cancer (PC) is successfully treated with anti-androgens; however, a significant proportion of patients develop resistance against this therapy. Anti-androgen-resistant disease (castration-resistant prostate cancer; CRPC) currently incurable. Cyclin-dependent kinase 7 (CDK7) positioned to positively regulate both cell cycle and transcription, the two features critical for rapid proliferation CRPC cells. Here, we assess if CDK7 viable target halt Methods We use...
Abstract Hyper-activation of transcription is frequent in cancer, which often leads to increased sensitivity compounds targeting the transcriptional kinases, particular cyclin-dependent kinase 9 (CDK9). However, mechanistic details as why CDK9 inhibition selectively kills cancer cells remain largely unknown. Here, we report that activates innate immune response through viral mimicry. In MYC over-expressing prostate cells, excessive accumulation mis-spliced RNA. Double-stranded RNA...
Abstract Fibrosis, neurodegeneration and cerebral angiomatosis (FINCA) is a childhood-onset multi-organ neurodevelopmental disorder associated with manifestations recurrent infections. The disease caused by variants in NHLRC2 initiating cascade of unknown pathological events. Previously, we have demonstrated that despite the significant decrease at molecular level, compound heterozygosity knock out p.Asp148Tyr alleles does not lead to severe phenotype mice. Here, analysed behavioural...
Abstract Prostate cancer (PC) is the most common in men and after development of castration-resistant PC (CRPC), there are no curative treatment options. Inactivating mutations cyclin-dependent kinase 12 (CDK12) define an aggressive sub-type CRPC. We hypothesized that compromised CDK12 activity leads to significant rewiring CRPC cells, this results actionable synthetic lethal interactions. Methods used combinatorial screening, ChIP-seq data, RNA-seq global alternative splicing analysis,...