Exploring the Influence of Parameters on the p53 Response When Single-Stranded Breaks and Double-Stranded Breaks Coexist

AbstractThe p53 response to DNA damage is closely related to cell fate decisions. P53 preferentially responds to single-stranded breaks (SSBs) exhibiting a graded response when single-stranded breaks (SSBs) and double-stranded breaks (DSBs) coexist. However, how p53 natural preferential response is affected by kinetic parameters remains to be elucidated. Here, based on the hybrid model I, we computationally searched all the parameters and parameter combinations in the parameter space to identify those that could alter the natural preferential response of p53 when SSBs and DSBs coexist. Firstly, when a single parameter is changed, the parameters that can alter graded response to produce p53 pulse response are production rate of ATM- and Rad3-related kinase(ATR) (beta2), ATR degradation rate (alf2) and ATR-dependent p53 production rate (beta31). Secondly, when double parameters are changed, the combinations of beta2/alf2/beta31 and any other parameters are capable of altering the p53 natural preferential response, and the combination of ataxia-telangiectasia mutated kinase (ATM)-dependent p53 production rate (beta3) and Wip1-dependent p53 degradation rate (alf35) is also capable of altering the p53 natural preferential response. Thirdly, we analyzed the sensitivity of both pulse amplitude and apoptosis to kinetic parameters. We find that pulse amplitude is most sensitive to ATM-dependent p53 production rate (beta3), and apoptosis is more sensitive to damage-dependent ATM produc...
Source: Interdisciplinary Sciences, Computational Life Sciences - Category: Bioinformatics Source Type: research

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Franchitto Conflicts between replication and transcription are a common source of genomic instability, a characteristic of almost all human cancers. Aberrant R-loops can cause a block to replication fork progression. A growing number of factors are involved in the resolution of these harmful structures and many perhaps are still unknown. Here, we reveal that the Werner interacting protein 1 (WRNIP1)-mediated response is implicated in counteracting aberrant R-loop accumulation. Using human cellular models with compromised Ataxia-Telangiectasia and Rad3-Related (ATR)-dependent checkpoint activation, we show that WRNIP1...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Publication date: 4 February 2020Source: Cell Reports, Volume 30, Issue 5Author(s): Katerina D. Fagan-Solis, Dennis A. Simpson, Rashmi J. Kumar, Luciano G. Martelotto, Lisle E. Mose, Naim U. Rashid, Alice Y. Ho, Simon N. Powell, Y. Hannah Wen, Joel S. Parker, Jorge S. Reis-Filho, John H.J. Petrini, Gaorav P. GuptaSummaryThe Mre11-Rad50-Nbs1 complex is a DNA double-strand break sensor that mediates a tumor-suppressive DNA damage response (DDR) in cells undergoing oncogenic stress, yet the mechanisms underlying this effect are poorly understood. Using a genetically inducible primary mammary epithelial cell model, we demonstr...
Source: Cell Reports - Category: Cytology Source Type: research
Abstract Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor with protein kinase activity,is frequently altered in human cancers including mantle cell lymphoma (MCL). Loss of ATM protein is linked to accumulation of nonfunctional mitochondria and defective mitophagy, in both murine thymocytes and in A-T cells. However, the mechanistic role of ATM kinase in cancer cell mitophagy is unknown. Here, we provide evidence that FCCP-induced mitophagy in MCL and other cancer cell lines is dependent on ATM but independent of its kinase function. While Granta-519 MCL cells possess single copy and kinase dead AT...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research
PA Abstract BACKGROUND: Bing-Neel syndrome is a rare neurological manifestation of Waldenström's macroglobulinaemia that can occur both before and after the diagnosis is set. CASE PRESENTATION: A man in his seventies with Waldenström's macroglobulinaemia under treatment with ibrutinib contacted the outpatient clinic due to bilateral pain distal to the knees. We initially suspected it was a side effect of ibrutinib and discontinued the drug. A few days later, he returned with reduced general condition, fever, shivers and a limping gait, and was hospitalised. Clinical examination revealed only pulmon...
Source: Tidsskrift for den Norske Laegeforening - Category: General Medicine Authors: Tags: Tidsskr Nor Laegeforen Source Type: research
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...
Source: Trends in Genetics - Category: Genetics & Stem Cells Source Type: research
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
This article describes the epidemiology, clinical presentation, diagnostic considerations, imaging findings, treatment, and prognosis of autoimmune disorders, in which the vestibulocerebellar syndrome is the main or presenting clinical presentation. Antibodies specific for intracellular antigenic targets described in the article are PCA-1 (Purkinje cell cytoplasmic antibody type 1, also known as anti-Yo), ANNA-1 (antinuclear neuronal antibody type 1, also known as anti-Hu), ANNA-2 (antinuclear neuronal antibody type 2, also known as anti-Ri), Ma1/2 (anti-Kelch-like 11/12 antibody), Kelch-like 11, amphiphysin, CV2 (collapsi...
Source: Seminars in Neurology - Category: Neurology Authors: Tags: Review Article Source Type: research
Conclusions KLHL11-abs associate with a spectrum of syndromes and tumors wider than those previously reported; 44% of patients have concurrent neuronal antibodies, some of them (anti-NMDAR) pathogenically relevant. Brain immunostaining is not useful for routine screening of KLHL11-abs.
Source: Neurology Neuroimmunology and Neuroinflammation - Category: Neurology Authors: Tags: Autoimmune diseases, All Clinical Neurology, Paraneoplastic syndrome Article Source Type: research
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