Transcriptional Regulation at DSBs: Mechanisms and Consequences

Publication date: Available online 28 January 2020Source: Trends in GeneticsAuthor(s): Feras E. Machour, Nabieh AyoubDefective double-strand break (DSB) repair leads to genomic instabilities that may augment carcinogenesis. DSBs trigger transient transcriptional silencing in the vicinity of transcriptionally active genes through multilayered processes instigated by Ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and poly-(ADP-ribose) polymerase 1 (PARP1). Novel factors have been identified that ensure DSB-induced silencing via two distinct pathways: direct inhibition of RNA Polymerase II (Pol II) mediated by negative elongation factor (NELF), and histone code editing by CDYL1 and histone deacetylases (HDACs) that catalyze H3K27me3 and erase lysine crotonylation, respectively. Here, we highlight major advances in understanding the mechanisms underlying transcriptional silencing at DSBs, and discuss its functional implications on repair. Furthermore, we discuss consequential links between DSB-silencing factors and carcinogenesis and discuss the potential of exploiting them for targeted cancer therapy.
Source: Trends in Genetics - Category: Genetics & Stem Cells Source Type: research

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Abstract Defective double-strand break (DSB) repair leads to genomic instabilities that may augment carcinogenesis. DSBs trigger transient transcriptional silencing in the vicinity of transcriptionally active genes through multilayered processes instigated by Ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and poly-(ADP-ribose) polymerase 1 (PARP1). Novel factors have been identified that ensure DSB-induced silencing via two distinct pathways: direct inhibition of RNA Polymerase II (Pol II) mediated by negative elongation factor (NELF), and histone code editing by CDYL1 and histone deac...
Source: Trends in Genetics : TIG - Category: Genetics & Stem Cells Authors: Tags: Trends Genet Source Type: research
Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/ Longevity Industry Consulting Services Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out m...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
The J.P. Morgan Healthcare conference runs every year in San Francisco, a big draw for the biotech industry, and many organizations take the opportunity to host events at the same time. Among these, the SENS Research Foundation has for the past few years hosted a pitch day in which biotech companies in the longevity industry, largely startups, present to that portion of the Bay Area investor community interested in funding the treatment of aging as a medical condition. I was there to present on progress at Repair Biotechnologies, and took some notes on the other companies as they talked about their work. Kimera Labs ...
Source: Fight Aging! - Category: Research Authors: Tags: Investment Source Type: blogs
Publication date: Available online 11 December 2019Source: Pharmacology &TherapeuticsAuthor(s): Alice Bradbury, Sally Hall, Nicola Curtin, Yvette DrewAbstractThe DNA damage response (DDR) machinery is responsible for detecting DNA damage, pausing the cell cycle and initiating DNA repair. Ataxia telangiectasia and Rad3-related (ATR) protein is a key kinase at the heart of the DDR, responsible for sensing replication stress (RS) and signalling it to S and G2/M checkpoints to facilitate repair. In cancer, loss of G1 checkpoint control and activation of oncogenes that drive replication, result in cancer cells more likely t...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research
Abstract Homologous recombination (HR) is a pathway to faithfully repair DNA double-strand breaks (DSBs). At the core of this pathway is a DNA recombinase, which, as a nucleoprotein filament on ssDNA, pairs with homologous DNA as a template to repair the damaged site. In eukaryotes Rad51 is the recombinase capable of carrying out essential steps including strand invasion, homology search on the sister chromatid and strand exchange. Importantly, a tightly regulated process involving many protein factors has evolved to ensure proper localisation of this DNA repair machinery and its correct timing within the cell cyc...
Source: Cellular and Molecular Life Sciences : CMLS - Category: Cytology Authors: Tags: Cell Mol Life Sci Source Type: research
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Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
This study showed that potential vicious cycles underlying ARDs are quite diverse and unique, triggered by diverse and unique factors that do not usually progress with age, thus casting doubts on the possibility of discovering the single molecular cause of aging and developing the single anti-aging pill. Rather, each disease appears to require an individual approach. However, it still cannot be excluded that some or all of these cycles are triggered by fundamental processes of aging, such as chronic inflammation or accumulation of senescent cells. Nevertheless, experimental data showing clear cause and effect relationships...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In this study, eight new Torin2 analogs were designed and synthesized through multistep synthesis. All the synthesized compounds were characterized by NMR and mass analysis. The newly synthesized analogs were evaluated for their anti-cancer activity via CellTiter-Glo® assay. Additionally, compounds 13 and 14 also showed significant inhibition for ATR and mTOR substrates, i.e., p-Chk1 Ser 317 and p70 S6K Thr 389, respectively. Compounds 13 and 14 displayed promising anti-cancer activity with HCT-116 cell lines in the preliminary study. Further, a comparative model of ATR kinase was generated using the SWISS-MODEL server...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
CONCLUSIONS: These results demonstrate that IR deregulates microRNA expression, affecting the DSB repair efficiency of irradiated thyroid cells, and suggest that miR-10b-5p overexpression may be an innovative approach for anaplastic thyroid cancer therapy by increasing cancer cell radiosensitivity. PMID: 29397781 [PubMed - as supplied by publisher]
Source: Thyroid : official journal of the American Thyroid Association - Category: Endocrinology Tags: Thyroid Source Type: research
Abstract Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptot...
Source: Current Medicinal Chemistry - Category: Chemistry Authors: Tags: Curr Med Chem Source Type: research
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