scholarly journals BRCA1-BARD1 regulates transcription through modulating topoisomerase IIβ

Open Biology ◽  
2021 ◽  
Vol 11 (10) ◽  
Author(s):  
Heeyoun Bunch ◽  
Jaehyeon Jeong ◽  
Keunsoo Kang ◽  
Doo Sin Jo ◽  
Anh T. Q. Cong ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Gene Activation ◽  
Strand Break ◽  
The Novel ◽  
Ataxia Telangiectasia Mutated ◽  
Protein Coding ◽  
Pol Ii ◽  
Dna Strand Break ◽  
Dna Strand ◽  
Inducible Genes

RNA polymerase II (Pol II)-dependent transcription in stimulus-inducible genes requires topoisomerase IIβ (TOP2B)-mediated DNA strand break and the activation of DNA damage response signalling in humans. Here, we report a novel function of the breast cancer 1 (BRCA1)-BRCA1-associated ring domain 1 (BARD1) complex in this process. We found that BRCA1 is phosphorylated at S1524 by the kinases ataxia-telangiectasia mutated and ATR during gene activation, and that this event is important for productive transcription. Our biochemical and genomic analyses showed that the BRCA1-BARD1 complex interacts with TOP2B in the EGR1 transcription start site and in a large number of protein-coding genes. Intriguingly, the BRCA1-BARD1 complex ubiquitinates TOP2B, which stabilizes TOP2B binding to DNA while BRCA1 phosphorylation at S1524 controls the TOP2B ubiquitination by the complex. Together, these findings suggest the novel function of the BRCA1-BARD1 complex in the regulation of TOP2B and Pol II-mediated gene expression.

scholarly journals BRCA1-BARD1 regulates transcription through modulating topoisomerase IIβ

2020 ◽  
Author(s):  
Jaehyeon Jeong ◽  
Keunsoo Kang ◽  
Doo Sin Jo ◽  
Anh T Cong ◽  
Donguk Kim ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Gene Activation ◽  
Strand Break ◽  
Protein Coding ◽  
Pol Ii ◽  
Dna Strand Break ◽  
Biochemical Analyses ◽  
Dna Strand ◽  
Inducible Genes

RNA polymerase II (Pol II)-dependent transcription in stimulus-inducible genes requires topoisomerase IIβ (TOP2B)-mediated DNA strand break and the activation of DNA damage response signaling in humans. Here, we report a novel function of the breast cancer 1 (BRCA1)-BRCA1 associated ring domain 1 (BARD1) complex, in this process. We found that BRCA1 is phosphorylated at S1524 by the kinases ATM and ATR during gene activation and that this event is essential for productive transcription. Our in vitro biochemical analyses showed TOP2B and BARD1 interaction and colocalization in the EGR1 transcription start site (TSS) and that the BRCA1-BARD1 complex ubiquitinates TOP2B, which appears to stabilize TOP2B protein in the cell and binding to DNA. Intriguingly, BRCA1 phosphorylation at S1524 controls this interaction. In addition, genomic analyses indicated colocalization between TOP2B and BRCA1 in a large number of protein-coding genes. Together, these findings reveal the novel function of the BRCA1-BARD1 complex in gene expression and in the regulation of TOP2B during Pol II transcription.

The invariance of the total direct DNA strand break yield

2011 ◽  
Vol 38 (7) ◽  
pp. 4147-4153 ◽  
Author(s):  
M. A. Bernal ◽  
C. E. deAlmeida ◽  
C. Sampaio ◽  
S. Incerti ◽  
C. Champion ◽  
...  
Keyword(s):  
Strand Break ◽  
Dna Strand Break ◽  
Dna Strand ◽  
Break Yield

scholarly journals Particle characterization and toxicity in C57BL/6 mice following instillation of five different diesel exhaust particles designed to differ in physicochemical properties

2020 ◽  
Author(s):  
Katja Maria Bendtsen ◽  
Louise Gren ◽  
Vilhelm Berg Malmborg ◽  
Pravesh Chandra Shukla ◽  
Martin Tunér ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Diesel Exhaust ◽  
Strand Break ◽  
Diesel Exhaust Particles ◽  
Ultra Low Sulfur Diesel ◽  
Dna Strand Break ◽  
Diesel Particles ◽  
Exhaust Particles ◽  
Dna Strand ◽  
Low Sulfur

Abstract Background Diesel exhaust is carcinogenic and exposure to diesel particles cause health effects. We investigated the toxicity of diesel exhaust particles designed to have varying physicochemical properties in order to attribute health effects to specific particle characteristics. Particles from three fuel types were compared at 13% engine intake O 2 concentration: MK1 ultra low sulfur diesel (DEP13) and the two renewable diesel fuels hydrotreated vegetable oil (HVO13) and rapeseed methyl ester (RME13). Additionally, diesel particles from MK1 ultra low sulfur diesel were generated at 9.7% (DEP9.7) and 17% (DEP17) intake O 2 concentration. We evaluated physicochemical properties and histopathological, inflammatory and genotoxic responses on day 1, 28 and 90 after single intratracheal instillation in mice compared to reference diesel particles and carbon black.Results Moderate variations were seen in physical properties for the five particles: primary particle diameter: 15-22 nm, specific surface area: 152-222 m 2 /g, and count median mobility diameter: 55-103 nm. Larger differences were found in chemical composition: organic carbon/total carbon ratio (0.12-0.60), polycyclic aromatic hydrocarbon content (1-27 mg/mg) and acid-extractable metal content (0.9-16 mg/mg). Intratracheal exposure to all five particles induced similar toxicological responses, with different potency. Lung particle retention was observed in DEP13 and HVO13 exposed mice on day 28, with less retention for the other fuel types. RME exposure induced limited response whereas the remaining particles induced dose-dependent inflammation and acute phase response on day 1. DEP13 induced acute phase response on day 28 and inflammation on day 90. DNA strand break levels were not increased as compared to vehicle, but were increased in lung and liver compared to blank filter extraction control. Neutrophil influx on day 1 correlated best with estimated deposited surface area, but also with elemental carbon, organic carbon and PAHs. DNA strand break levels in liver on day 90 correlated with acellular particle-induced ROS.Conclusions We studied diesel exhaust particles designed to differ in physicochemical properties. Our study highlights particle size, elemental carbon content, PAHs and ROS-generating potential as physicochemical predictors of diesel particle toxicity.

scholarly journals CTCF Interacts with and Recruits the Largest Subunit of RNA Polymerase II to CTCF Target Sites Genome-Wide

2007 ◽  
Vol 27 (5) ◽  
pp. 1631-1648 ◽  
Author(s):  
Igor Chernukhin ◽  
Shaharum Shamsuddin ◽  
Sung Yun Kang ◽  
Rosita Bergström ◽  
Yoo-Wook Kwon ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Gene Activation ◽  
Ctcf Binding ◽  
Pol Ii ◽  
Genome Wide ◽  
Target Sites ◽  
On Chip

ABSTRACT CTCF is a transcription factor with highly versatile functions ranging from gene activation and repression to the regulation of insulator function and imprinting. Although many of these functions rely on CTCF-DNA interactions, it is an emerging realization that CTCF-dependent molecular processes involve CTCF interactions with other proteins. In this study, we report the association of a subpopulation of CTCF with the RNA polymerase II (Pol II) protein complex. We identified the largest subunit of Pol II (LS Pol II) as a protein significantly colocalizing with CTCF in the nucleus and specifically interacting with CTCF in vivo and in vitro. The role of CTCF as a link between DNA and LS Pol II has been reinforced by the observation that the association of LS Pol II with CTCF target sites in vivo depends on intact CTCF binding sequences. “Serial” chromatin immunoprecipitation (ChIP) analysis revealed that both CTCF and LS Pol II were present at the β-globin insulator in proliferating HD3 cells but not in differentiated globin synthesizing HD3 cells. Further, a single wild-type CTCF target site (N-Myc-CTCF), but not the mutant site deficient for CTCF binding, was sufficient to activate the transcription from the promoterless reporter gene in stably transfected cells. Finally, a ChIP-on-ChIP hybridization assay using microarrays of a library of CTCF target sites revealed that many intergenic CTCF target sequences interacted with both CTCF and LS Pol II. We discuss the possible implications of our observations with respect to plausible mechanisms of transcriptional regulation via a CTCF-mediated direct link of LS Pol II to the DNA.

Sign in / Sign up

Export Citation Format

Share Document