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Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription

ABSTRACT: Regulation of global transcription output is important for normal development and disease but only few regulators of the process are known. Here, we describe DNA topoisomerase I (TOP1) as a novel regulator where it exerts transcriptional repression to prevent transcription overdrive. This function requires a conserved secondary DNA binding surface that is distinct from its catalytic pocket.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE207163 | GEO | 2023/05/29

REPOSITORIES: GEO

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Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription.

Project description:Regulation of global transcription output is important for normal development and disease, but little is known about the mechanisms involved. DNA topoisomerase I (TOP1) is an enzyme well-known for its role in relieving DNA supercoils for enabling transcription. Here, we report a non-enzymatic function of TOP1 that downregulates RNA synthesis. This function is dependent on specific DNA-interacting residues located on a conserved protein surface. A loss-of-function knock-in mutation on this surface, R548Q, is sufficient to cause hypertranscription and alter differentiation outcomes in mouse embryonic stem cells (mESCs). Hypertranscription in mESCs is accompanied by reduced TOP1 chromatin binding and change in genomic supercoiling. Notably, the mutation does not impact TOP1 enzymatic activity; rather, it diminishes TOP1-DNA binding and formation of compact protein-DNA structures. Thus, TOP1 exhibits opposing influences on transcription through distinct activities which are likely to be coordinated. This highlights TOP1 as a safeguard of appropriate total transcription levels in cells.

| S-EPMC10576097 | biostudies-literature

Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription

Project description:Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription

| PRJNA854061 | ENA

TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts

Project description:Eukaryotic topoisomerase 1 (TOP1) regulates DNA topology to ensure efficient DNA replication and transcription. TOP1 is also a major driver of endogenous genome instability, particularly when its catalytic intermediate - a covalent TOP1-DNA adduct known as a TOP1 cleavage complex (TOP1cc) - is stabilised. TOP1ccs are highly cytotoxic and a failure to resolve them underlies the pathology of neurological disorders but is also exploited in cancer therapy where TOP1ccs are the target of widely used frontline anti-cancer drugs. A critical enzyme for TOP1cc resolution is the tyrosyl-DNA phosphodiesterase, TDP1, which hydrolyses the bond that links a tyrosine in the active site of TOP1 to a 3’ phosphate group on a single-stranded (ss)DNA break. However, TDP1 can only process small peptide fragments from ssDNA ends, raising the question of how the ~90 kDa TOP1 protein is processed upstream of TDP1. We find that TEX264 fulfils this role by forming a complex with the p97 ATPase and the SPRTN metalloprotease. We show that TEX264 recognises both unmodified and SUMO1-modifed TOP1 and initiates TOP1cc repair by recruiting p97 and SPRTN. TEX264 localises to the nuclear periphery, associates with DNA replication forks, and counteracts TOP1ccs during DNA replication. Altogether, our study elucidates the existence of a specialised repair complex required for upstream proteolysis of TOP1ccs and their subsequent resolution.

2020-03-13 | PXD017239 | Pride

G-quadruplex on Chromosomal DNA Negatively Regulates Topoisomerase 1 Activity [CUT&Tag]

Project description:Human DNA topoisomerase 1 (Top1) is a crucial enzyme responsible for alleviating torsional stress on DNA during transcription and replication, thereby maintaining genome stability. Previous researches had found that non-working Top1 interacted extensively with chromosomal DNA in human cells. However, the reason for its retention on chromosomal DNA remained unclear. In this study, we discovered a close association between Top1 and chromosomal DNA, specifically linked to the presence of G-quadruplex (G4) structures. G4 structures, formed during transcription, trap Top1 and hinder its ability to relax neighboring DNAs. Disruption of the Top1-G4 interaction using G4 ligand relieved the inhibitory effect of G4 on Top1 activity, resulting in a further reduction of R-loop levels in cells. Additionally, the activation of Top1 through the use of a G4 ligand enhanced the toxicity of Top1 inhibitors towards cancer cells. Our study uncovers a negative regulation mechanism of human Top1 and highlights a novel pathway for activating Top1.

2024-01-01 | GSE239690 | GEO

G-quadruplex on Chromosomal DNA Negatively Regulates Topoisomerase 1 Activity [ChIP-seq]

2024-01-01 | GSE239692 | GEO

RNA Interacts with Topoisomerase I to Modulate its Catalytic Activity

Project description:Topoisomerase I (TOP1) is an essential enzyme that relaxes DNA to prevent and dissipate torsional stress during transcription. However, the mechanisms underlying the regulation of TOP1 activity remain elusive. Using eCLIP and UV-RIP-seq we identify TOP1 as a RNA binding protein (RBP). Using a TOP1 RNA binding mutant and TOP1cc-seq to map TOP1 catalytic activity, we reveal that RNA opposes TOP1 activity as RNAPII commences transcription of active genes. These findings support new insights into the coordinated actions of RNA and TOP1 in regulating DNA topological stress intrinsic to RNAPII-dependent transcription.

2024-08-21 | GSE213403 | GEO

GRO analysis of topoisomerase mutants

Project description:Genomic Run-on analysis of topoisomerase mutants (top1-delta/top2ts or top2ts) has been conducted at reference temperature for wt strain and at non-permissive temperature for wt and mutant strains. Keywords: Genomic Run On The analysis includes 3 repeats of the wild type strain (JCW25) at 30ÂºC and 3 more at 37ÂºC, 3 repeats of the top2ts mutant (JCW26) at 37ÂºC and 3 repeats of the double top1 (delta) top2ts mutant at 37ÂºC. A single genomic DNA hybridization on one of the filters can be used for normalization between gene probes if needed.

2010-06-24 | E-GEOD-16673 | biostudies-arrayexpress

GRO analysis of topoisomerase mutants

2010-02-16 | GSE16673 | GEO

Study of Topoisomerase I in human

Project description:We report a mechanism through which the transcription machinery directly controls topoisomerase 1 (TOP1) activity to adjust DNA topology throughout the transcription cycle. By comparing TOP1 occupancy using ChIP-Seq, versus TOP1 activity using TOP1-Seq, a method reported here to map catalytically engaged TOP1, TOP1 bound at promoters was discovered to become fully active only after pause-release. This transition coupled the phosphorylation of the carboxyl-terminal-domain (CTD) of RNA polymerase II (RNAPII) with stimulation of TOP1 above its basal rate, enhancing its processivity. TOP1 stimulation is strongly dependent on the kinase activity of BRD4, a protein that phosphorylates Ser2-CTD and regulates RNAPII pause-release. Thus the coordinated action of BRD4 and TOP1 overcame the torsional stress opposing transcription as RNAPII commenced elongation, but preserved negative supercoiling that assists promoter melting at start sites. This nexus between transcription and DNA topology promises to elicit new strategies to intercept pathological gene expression.

2016-04-12 | GSE57628 | GEO

Co-ordinate inhibiton of autism candidate genes by topoisomerase inhibitors [array]

Project description:Topoisomerases are necessary for the expression of neurodevelopmental genes, and are mutated in some patients with autism spectrum disorder (ASD). We have studied the effects of inhibitors of Topoisomerase 1 (Top1) and Topoisomerase 2 (Top2) enzymes on mouse cortical neurons. We find that topoisomerases selectively inhibit long genes (>100kb), with little effect on all other gene expression. Using ChIPseq against RNA Polymerase II (Pol2) we show that the Top1 inhibitor topotecan blocks transcriptional elongation of long genes specifically. Many of the genes inhibited by topotecan are candidate ASD genes, leading us to propose that topoisomerase inhibition might contribute to ASD pathology.

2013-08-30 | GSE43899 | GEO

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