Zeolite DDR Membranes

DDR nanocrystals of uniform size and structure were synthesized using hydrothermal secondary growth and then used to make DDR zeolite membranes and for any other use where uniform, small DDR zeolite crystals are beneficial.Georgia Tech Research Corporatio

Cell Death Response to DNA Damage.

The cell death response to DNA damage is discussed in this Perspectives piece with cancer as the backdrop because DNA damaging agents (DDA) are widely used to treat cancer. From decades of clinical results, we learn that DDA have cured some cancers but their toxicity is temporary in most cancers due to emergence of DDA-resistant cancer cells. Investigation of DDA-activated genes, proteins, and pathways, known collectively as the DNA damage response (DDR), has uncovered the inner workings of DDR that protect the genome to sustain life. Paradoxically, however, DDR can also activate death. Current knowledge on DDA-activated death and hypotheses for how DDR may determine when and where to execute death are discussed. Given that cancer cells suffer from DDR defects, which account for their initial sensitivity to DDA, future therapeutic development may exploit those cancer-specific DDR defects to selectively create death-inducing DNA lesions, without using DDA, to kill DDA-resistant cancers

Suppressor of gamma response 1 modulates the DNA damage response and oxidative stress response in leaves of cadmium-exposed Arabidopsis thaliana

Cadmium (Cd) exposure causes an oxidative challenge and inhibits cell cycle progression, ultimately impacting plant growth. Stress-induced effects on the cell cycle are often a consequence of activation of the DNA damage response (DDR). The main aim of this study was to investigate the role of the transcription factor SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1) and three downstream cyclin-dependent kinase inhibitors of the SIAMESE-RELATED (SMR) family in the Cd-induced DDR and oxidative challenge in leaves of Arabidopsis thaliana. Effects of Cd on plant growth, cell cycle regulation and the expression of DDR genes were highly similar between the wildtype and smr4/5/7 mutant. In contrast, sog1-7 mutant leaves displayed a much lower Cd sensitivity within the experimental time-frame and significantly less pronounced upregulations of DDR-related genes, indicating the involvement of SOG1 in the Cd-induced DDR. Cadmium-induced responses related to the oxidative challenge were disturbed in the sog1-7 mutant, as indicated by delayed Cd-induced increases of hydrogen peroxide and glutathione concentrations and lower upregulations of oxidative stress-related genes. In conclusion, our results attribute a novel role to SOG1 in regulating the oxidative stress response and connect oxidative stress to the DDR in Cd-exposed plants

The ubiquitin E3/E4 ligase, UBE4A, fine-tunes protein ubiquitylation and accumulation at sites of DNA damage facilitating double-strand break repair

Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning - the E3/E4 ubiquitin ligase, UBE4A. UBE4A’s recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end-resection at DSBs, and its abrogation leads to up-regulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning of the complex DDR network for accurate and balanced execution of DSB repai

A p53-independent role for the MDM2 antagonist Nutlin-3 in DNA damage response initiation.

BACKGROUND: The mammalian DNA-damage response (DDR) has evolved to protect genome stability and maximize cell survival following DNA-damage. One of the key regulators of the DDR is p53, itself tightly regulated by MDM2. Following double-strand DNA breaks (DSBs), mediators including ATM are recruited to the site of DNA-damage. Subsequent phosphorylation of p53 by ATM and ATM-induced CHK2 results in p53 stabilization, ultimately intensifying transcription of p53-responsive genes involved in DNA repair, cell-cycle checkpoint control and apoptosis. METHODS: In the current study, we investigated the stabilization and activation of p53 and associated DDR proteins in response to treatment of human colorectal cancer cells (HCT116p53+/+) with the MDM2 antagonist, Nutlin-3. RESULTS: Using immunoblotting, Nutlin-3 was observed to stabilize p53, and activate p53 target proteins. Unexpectedly, Nutlin-3 also mediated phosphorylation of p53 at key DNA-damage-specific serine residues (Ser15, 20 and 37). Furthermore, Nutlin-3 induced activation of CHK2 and ATM - proteins required for DNA-damage-dependent phosphorylation and activation of p53, and the phosphorylation of BRCA1 and H2AX - proteins known to be activated specifically in response to DNA damage. Indeed, using immunofluorescent labeling, Nutlin-3 was seen to induce formation of γH2AX foci, an early hallmark of the DDR. Moreover, Nutlin-3 induced phosphorylation of key DDR proteins, initiated cell cycle arrest and led to formation of γH2AX foci in cells lacking p53, whilst γH2AX foci were also noted in MDM2-deficient cells. CONCLUSION: To our knowledge, this is the first solid evidence showing a secondary role for Nutlin-3 as a DDR triggering agent, independent of p53 status, and unrelated to its role as an MDM2 antagonist

Germline and Somatic DNA Damage Repair Gene Mutations and Overall Survival in Metastatic Pancreatic Adenocarcinoma Patients Treated with FOLFIRINOX

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX. Experimental Design: Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical, and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analysis was conducted using Kaplan–Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage. Results: Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 (N = 7), BRCA2 (N = 5), PALB2 (N = 3), MSH2 (N = 1), and FANCF (N = 1) of all the DDR genes sequenced. Median age was 65.5 years, 58% were male, 97.2% were Caucasian and 51.4% had any family history of cancer. The median OS was near significantly superior in those with DDR gene mutations present vs. absent [14 vs. 5 months; HR, 0.58; 95% confidence interval (CI), 0.29–1.14; log-rank P = 0.08]. Multivariate logistic (OR, 1.47; 95% CI, 1.04–2.06; P = 0.04) and Cox regression (HR, 0.37; 95% CI, 0.15–0.94; P = 0.04) showed presence of DDR gene mutations was associated with improved OS. Conclusions: In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX

Disarmament, Demobilization, and Reintegration: The co-evolution of concepts, practices, and understanding

Programs for the Disarmament, Demobilization, and Reintegration (DDR) of ex-combatants have become more common as an element in the peacebuilder’s toolkit. They have evolved over the last 15 years, and can interact positively with an ongoing peace process. The literature assessing DDR is reviewed in this paper. Results have not always been positive, however. Despite recognition of the need for a more holistic, integrated approach, there are real challenges in implementing such a complex program in a post-conflict environment. Qualitative studies have highlighted these difficulties, and the few quantitative assessments of the outcomes are mixed. However, understanding of DDR is being advanced by a rich policy literature, together with specific “best practice” studies. Recognition of the importance of a participatory approach, and ownership of the process by the beneficiaries, has added to this understanding. The paper concludes that DDR is set to remain an important tool, and that it is most effective when used flexibly, appropriately, and with the genuine participation of those it is supposed to benefit