Loss of mouse Stmn2 function causes motor neuropathy.

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration accompanied by aberrant accumulation and loss of function of the RNA-binding protein TDP43. Thus far, it remains unresolved to what extent TDP43 loss of function directly contributes to motor system dysfunction. Here, we employed gene editing to find whether the mouse ortholog of the TDP43-regulated gene STMN2 has an important function in maintaining the motor system.

Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML.

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2-mutant (STAG2-mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells.

FANCD2 Maintains Fork Stability in BRCA1/2-Deficient Tumors and Promotes Alternative End-Joining DNA Repair.

BRCA1/2 proteins function in homologous recombination (HR)-mediated DNA repair and cooperate with Fanconi anemia (FA) proteins to maintain genomic integrity through replication fork stabilization. Loss of BRCA1/2 proteins results in DNA repair deficiency and replicative stress, leading to genomic instability and enhanced sensitivity to DNA-damaging agents. Recent studies have shown that BRCA1/2-deficient tumors upregulate Polθ-mediated alternative end-joining (alt-EJ) repair as a survival mechanism.

The cytotoxicity and genotoxicity of soluble and particulate cobalt in human lung epithelial cells.

Cobalt is a toxic metal used in various industrial applications leading to adverse lung effects by inhalation. Cobalt is considered a possible human carcinogen with the lung being a primary target. However, few studies have considered cobalt-induced toxicity in human lung cells, especially normal lung epithelial cells.

Hexavalent chromium induces chromosome instability in human urothelial cells.

Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants.

Chronic Exposure to Particulate Chromate Induces Premature Centrosome Separation and Centriole Disengagement in Human Lung Cells.

Particulate hexavalent chromium (Cr(VI)) is a well-established human lung carcinogen. Lung tumors are characterized by structural and numerical chromosome instability. Centrosome amplification is a phenotype commonly found in solid tumors, including lung tumors, which strongly correlates with chromosome instability.

Human Skin Cells Are More Sensitive than Human Lung Cells to the Cytotoxic and Cell Cycle Arresting Impacts of Particulate and Soluble Hexavalent Chromium.

Hexavalent chromium Cr(VI) is a known human lung carcinogen, with solubility playing an important role in its carcinogenic potency. Dermal exposure to Cr(VI) is common and has been associated with skin damage; however, no link between chromate exposure and skin cancer has been found. In this study, we compared the cytotoxic and clastogenic effects of Cr(VI) and its impacts on cell cycle progression in human lung and skin fibroblasts.

Homologous recombination repair signaling in chemical carcinogenesis: prolonged particulate hexavalent chromium exposure suppresses the Rad51 response in human lung cells.

The aim of this study was to focus on hexavalent chromium, [Cr(VI)], a chemical carcinogen and major public health concern, and consider its ability to impact DNA double strand break repair. We further focused on particulate Cr(VI), because it is the more potent carcinogenic form of Cr(VI). DNA double strand break repair serves to protect cells against the detrimental effects of DNA double strand breaks.

The cytotoxicity and genotoxicity of soluble and particulate cobalt in human lung fibroblast cells.

Cobalt exposure is increasing as cobalt demand rises worldwide due to its use in enhancing rechargeable battery efficiency, super-alloys, and magnetic products. Cobalt is considered a possible human carcinogen with the lung being a primary target. However, few studies have considered cobalt-induced toxicity in human lung cells.

The impact of homologous recombination repair deficiency on depleted uranium clastogenicity in Chinese hamster ovary cells: XRCC3 protects cells from chromosome aberrations, but increases chromosome fragmentation.

Depleted uranium (DU) is extensively used in both industry and military applications. The potential for civilian and military personnel exposure to DU is rising, but there are limited data on the potential health hazards of DU exposure. Previous laboratory research indicates DU is a potential carcinogen, but epidemiological studies remain inconclusive.

Protein tyrosine phosphatase (PTP) inhibition enhances chromosomal stability after genotoxic stress: decreased chromosomal instability (CIN) at the expense of enhanced genomic instability (GIN)?

Inappropriate survival signaling after DNA damage may facilitate clonal expansion of genetically compromised cells, and it is known that protein tyrosine phosphatase (PTP) inhibitors activate key survival pathways. In this study we employed the genotoxicant, hexavalent chromium [Cr(VI)], which is a well-documented carcinogen of occupational and environmental concern. Cr(VI) induces a complex array of DNA damage, including DNA double strand breaks (DSBs).

Comparative cytotoxicity and genotoxicity of particulate and soluble hexavalent chromium in human and sperm whale (Physeter macrocephalus) skin cells.

Chromium (Cr) is a global marine pollutant, present in marine mammal tissues. Hexavalent chromium [Cr(VI)] is a known human carcinogen. In this study, we compare the cytotoxic and clastogenic effects of Cr(VI) in human (Homo sapiens) and sperm whale (Physeter macrocephalus) skin fibroblasts.

Mechanisms of metal-induced centrosome amplification.

Exposure to toxic and carcinogenic metals is widespread; however, their mechanisms of action remain largely unknown. One potential mechanism for metal-induced carcinogenicity and toxicity is centrosome amplification. Here we review the mechanisms for metal-induced centrosome amplification, including arsenic, chromium, mercury and nano-titanium dioxide.

The cytotoxicity and genotoxicity of hexavalent chromium in Steller sea lion lung fibroblasts compared to human lung fibroblasts.

In this study we directly compared soluble and particulate chromate cytotoxicity and genotoxicity in human (Homo sapiens) and sea lion (Eumetopias jubatus) lung fibroblasts. Our results show that hexavalent chromium induces increased cell death and chromosome damage in both human and sea lion cells with increasing intracellular chromium ion levels. The data further indicate that both sodium chromate and lead chromate are less cytotoxic and genotoxic to sea lion cells than human cells, based on an administered dose.

Chronic exposure to zinc chromate induces centrosome amplification and spindle assembly checkpoint bypass in human lung fibroblasts.

Hexavalent chromium (Cr(VI)) compounds are known human lung carcinogens. Solubility plays an important role in its carcinogenicity with the particulate or insoluble form being the most potent. Of the particulate Cr(VI) compounds, zinc chromate appears to be the most potent carcinogen; however, very few studies have investigated its carcinogenic mechanism.

Comparative genotoxicity and cytotoxicity of four hexavalent chromium compounds in human bronchial cells.

Hexavalent chromium (Cr(VI)) compounds are well-established human lung carcinogens. Solubility plays an important role in their carcinogenicity with the particulate Cr(VI) compounds being the most carcinogenic. Epidemiology and animal studies suggest that zinc chromate is the most potent particulate Cr(VI) compound; however, there are few comparative data to support these observations.

Cytotoxicity and genotoxicity of hexavalent chromium in human and North Atlantic right whale (Eubalaena glacialis) lung cells.

Humans and cetaceans are exposed to a wide range of contaminants. In this study, we compared the cytotoxic and genotoxic effects of a metal pollutant, hexavalent chromium [Cr(VI)], which has been shown to cause damage in lung cells from both humans and North Atlantic right whales. Our results show that Cr induces increased cell death and chromosome damage in lung cells from both species with increasing intracellular Cr ion levels.

Zinc chromate induces chromosome instability and DNA double strand breaks in human lung cells.

Hexavalent chromium Cr(VI) is a respiratory toxicant and carcinogen, with solubility playing an important role in its carcinogenic potential. Zinc chromate, a water insoluble or 'particulate' Cr(VI) compound, has been shown to be carcinogenic in epidemiology studies and to induce tumors in experimental animals, but its genotoxicity is poorly understood. Our study shows that zinc chromate induced concentration-dependent increases in cytotoxicity, chromosome damage and DNA double strand breaks in human lung cells.

Metal tissue levels in Steller sea lion (Eumetopias jubatus) pups.

The endangered Western population of the Steller sea lion declined for three decades for uncertain reasons. We present baseline data of metal concentrations in pups as a first step towards investigating the potential threat of developmental exposures to contaminants. Seven metals were investigated: arsenic, cadmium, silver, aluminum, mercury, lead and vanadium.

Hexavalent chromium-induced DNA damage and repair mechanisms.

Hexavalent chromium is a commonly used industrial metal that has been shown to induce lung cancer in workers having long term exposure. In the particulate form, Cr(VI) dissolves slowly in vivo, leading to an extended exposure of lung cells. Hexavalent chromium is taken into the cell and rapidly reduced to Cr(V), Cr(IV), Cr(III), and reactive oxygen species.

Neoplastic transformation of human bronchial cells by lead chromate particles.

Particulate hexavalent chromium (Cr(VI)) is a well-established human lung carcinogen with widespread exposure among people in occupational settings and the general public. However, no studies have examined the chromate-induced malignant transformation of human lung epithelial cells, its predominant target. Human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells were used to better understand the mechanisms involved in human bronchial carcinogenesis induced by particulate chromate.

Particulate and soluble hexavalent chromium are cytotoxic and genotoxic to human lung epithelial cells.

Particulate hexavalent chromium (Cr(VI)) is a well-established human lung carcinogen. It is currently a major public health concern, there is widespread exposure to it in occupational settings and to the general public. However, despite the potential widespread exposure and the fact that the lung is its target organ, few studies have considered the toxic effects of particulate Cr(VI) in human lung cells.

The clastogenic effects of chronic exposure to particulate and soluble Cr(VI) in human lung cells.

Hexavalent chromium (Cr(VI)) is a well-designated human lung carcinogen, with solubility playing an important role in its carcinogenic potential. Although it is known that particulate or water-insoluble Cr(VI) compounds are more potent than the soluble species of this metal, the mechanisms of action are not fully elucidated. In this study, we investigated the hypothesis that the difference in potency between particulate and soluble Cr(VI) is due to more chronic exposures with particulate chromate because it can deposit and persist in the lungs while soluble chromate is rapidly cleared.