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Cell Reports Jan 2024TREX2, a 3'-5' exonuclease, is a part of the DNA damage tolerance (DDT) pathway that stabilizes replication forks (RFs) by ubiquitinating PCNA along with the ubiquitin...
TREX2, a 3'-5' exonuclease, is a part of the DNA damage tolerance (DDT) pathway that stabilizes replication forks (RFs) by ubiquitinating PCNA along with the ubiquitin E3 ligase RAD18 and other DDT factors. Mismatch repair (MMR) corrects DNA polymerase errors, including base mismatches and slippage. Here we demonstrate that TREX2 deletion reduces mutations in cells upon exposure to genotoxins, including those that cause base lesions and DNA polymerase slippage. Importantly, we show that TREX2 generates most of the spontaneous mutations in MMR-mutant cells derived from mice and people. TREX2-induced mutagenesis is dependent on the nuclease and DNA-binding attributes of TREX2. RAD18 deletion also reduces spontaneous mutations in MMR-mutant cells, albeit to a lesser degree. Inactivation of both MMR and TREX2 additively increases RF stalls, while it decreases DNA breaks, consistent with a synthetic phenotype.
Topics: Humans; Mice; Animals; Mutagens; Mutagenesis; DNA-Directed DNA Polymerase; Mutation; Ubiquitin; DNA Replication; Exodeoxyribonucleases; Phosphoproteins; DNA-Binding Proteins; Ubiquitin-Protein Ligases
PubMed: 38175749
DOI: 10.1016/j.celrep.2023.113637 -
Blood Cancer Journal Sep 2023Rituximab-based chemo-immunotherapy is currently the standard first-line treatment for Waldenstrom macroglobulinaemia (WM), while ibrutinib has emerged as an... (Meta-Analysis)
Meta-Analysis
Rituximab-based chemo-immunotherapy is currently the standard first-line treatment for Waldenstrom macroglobulinaemia (WM), while ibrutinib has emerged as an alternative. In the absence of randomised trials (RCTs) comparing these regimens, the optimal first-line treatment for WM remains uncertain. In this systematic review and meta-analysis, we sought to assess the efficacy and safety of first-line treatment regimens for WM. We searched key databases from January 2007 to March 2023, including phase II and III trials, including treatment-naïve WM patients treated with rituximab-based regimens or ibrutinib. Response rates, progression-free survival (PFS), overall survival (OS), and toxicities were evaluated. Four phase III and seven phase II trials were included among 736 unique records. Pooled response rates from all comparative and non-comparative trials were 46%, 33% and 26% for bendamustine rituximab (BR), bortezomib-dexamethasone, cyclophosphamide, rituximab (BDRC) and ibrutinib rituximab (IR), respectively. Two-year pooled PFS was 89%, 81% and 82% with BR, BDRC and IR, respectively. Neuropathy was more frequent with bortezomib, while haematologic and cardiac toxicities were more common with chemo-immunotherapy and ibrutinib-based regimens respectively. Our findings suggest that BR yields higher response rates than bortezomib or ibrutinib-based combinations. RCTs comparing BR against emerging therapies, including novel Bruton Tyrosine Kinase Inhibitors, are warranted.
Topics: Humans; Waldenstrom Macroglobulinemia; Rituximab; Bortezomib; Clinical Protocols; Cyclophosphamide
PubMed: 37679351
DOI: 10.1038/s41408-023-00916-5 -
Communications Biology Dec 2023Arsenic enhances the carcinogenicity of ultraviolet radiation (UVR). However, the mechanisms of arsenic-driven oncogenesis are not well understood. Here, we utilize...
Arsenic enhances the carcinogenicity of ultraviolet radiation (UVR). However, the mechanisms of arsenic-driven oncogenesis are not well understood. Here, we utilize experimental systems to investigate the carcinogenic and mutagenic properties of co-exposure to arsenic and UVR. In vitro and in vivo exposures indicate that, by itself, arsenic is not mutagenic. However, in combination with UVR, arsenic exposure has a synergistic effect leading to an accelerated mouse skin carcinogenesis and to more than 2-fold enrichment of UVR mutational burden. Notably, mutational signature ID13, previously found only in UVR-associated human skin cancers, is observed exclusively in mouse skin tumors and cell lines jointly exposed to arsenic and UVR. This signature was not observed in any model system exposed purely to arsenic or purely to UVR, making ID13, to the best of our knowledge, the first co-exposure signature to be reported using controlled experimental conditions. Analysis of existing skin cancer genomics data reveals that only a subset of cancers harbor ID13 and these exhibit an elevated UVR mutagenesis. Our results report a unique mutational signature caused by a co-exposure to two environmental carcinogens and provide comprehensive evidence that arsenic is a potent co-mutagen and co-carcinogen of UVR.
Topics: Animals; Mice; Humans; Arsenic; Ultraviolet Rays; Mutagens; Skin Neoplasms; Skin
PubMed: 38104187
DOI: 10.1038/s42003-023-05659-4 -
Journal of Ayub Medical College,... 2023Primary ovarian Burkitt lymphoma (BL) is a very rare and aggressive malignancy. We report an 18-year-old female patient who presented with a large, tender abdomen, and...
Primary ovarian Burkitt lymphoma (BL) is a very rare and aggressive malignancy. We report an 18-year-old female patient who presented with a large, tender abdomen, and highly de-ranged renal and liver functions. Ultrasonography showed hepatosplenomegaly, mild ascites, dilated biliary channels and a heterogeneous pelvic mass of size ~15106.4 cm. Immunohistochemical (IHC) staining of the biopsy sample excised from the left ovary demonstrated reactivity for CD20 and CD10, and negativity for CD3, Bcl-2 and TdT. The C-myc translocation was positive in 60% of tumour cells. Moreover, the proliferation index was ~90%. These features were consistent with BL. After haemodialysis, the patient was planned for multiagent chemotherapy, including cyclophosphamide, doxorubicin, vincristine and prednisone. This case supports the hypothesis that primary ovarian BL is an aggressive malignancy that appears to respond promisingly to multi-agent chemotherapy.
Topics: Female; Humans; Adolescent; Burkitt Lymphoma; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Vincristine; Prednisone; Doxorubicin
PubMed: 38406915
DOI: 10.55519/JAMC-S4-12410 -
Cells Aug 2023Salinity stress affects plant growth and development by causing osmotic stress and nutrient imbalances through excess Na, K, and Cl ion accumulations that induce toxic... (Review)
Review
Salinity stress affects plant growth and development by causing osmotic stress and nutrient imbalances through excess Na, K, and Cl ion accumulations that induce toxic effects during germination, seedling development, vegetative growth, flowering, and fruit set. However, the effects of salt stress on growth and development processes, especially in polyploidized leguminous plants, remain unexplored and scantly reported compared to their diploid counterparts. This paper discusses the physiological and molecular response of legumes towards salinity stress-based osmotic and ionic imbalances in plant cells. A multigenic response involving various compatible solutes, osmolytes, ROS, polyamines, and antioxidant activity, together with genes encoding proteins involved in the signal transduction, regulation, and response mechanisms to this stress, were identified and discussed. This discussion reaffirms polyploidization as the driving force in plant evolution and adaptation to environmental stress constraints such as drought, feverish temperatures, and, in particular, salt stress. As a result, thorough physiological and molecular elucidation of the role of gene duplication through induced autopolyploidization and possible mechanisms regulating salinity stress tolerance in grain legumes must be further studied.
Topics: Fabaceae; Mutagens; Salt Tolerance; Salt Stress; Crops, Agricultural
PubMed: 37626892
DOI: 10.3390/cells12162082 -
Neoplasia (New York, N.Y.) Sep 2023Certain Enterobacteriaceae strains contain a 54-kb biosynthetic gene cluster referred to as "pks" encoding the biosynthesis of a secondary metabolite, colibactin....
Certain Enterobacteriaceae strains contain a 54-kb biosynthetic gene cluster referred to as "pks" encoding the biosynthesis of a secondary metabolite, colibactin. Colibactin-producing E. coli promote colorectal cancer (CRC) in preclinical models, and in vitro induce a specific mutational signature that is also detected in human CRC genomes. Yet, how colibactin exposure affects the mutational landscape of CRC in vivo remains unclear. Here we show that colibactin-producing E. coli-driven colonic tumors in mice have a significantly higher SBS burden and a larger percentage of these mutations can be attributed to a signature associated with mismatch repair deficiency (MMRd; SBS15), compared to tumors developed in the presence of colibactin-deficient E. coli. We found that the synthetic colibactin 742 but not an inactive analog 746 causes DNA damage and induces transcriptional activation of p53 and senescence signaling pathways in non-transformed human colonic epithelial cells. In MMRd colon cancer cells (HCT 116), chronic exposure to 742 resulted in the upregulation of BRCA1, Fanconi anemia, and MMR signaling pathways as revealed by global transcriptomic analysis. This was accompanied by increased T>N single-base substitutions (SBS) attributed to the proposed pksE. coli signature (SBS88), reactive oxygen species (SBS17), and mismatch-repair deficiency (SBS44). A significant co-occurrence between MMRd SBS44 and pks-associated SBS88 signature was observed in a large cohort of human CRC patients (n=2,945), and significantly more SBS44 mutations were found when SBS88 was also detected. Collectively, these findings reveal the host response mechanisms underlying colibactin genotoxic activity and suggest that colibactin may exacerbate MMRd-associated mutations.
Topics: Humans; Mice; Animals; Mutagens; Escherichia coli; DNA Mismatch Repair; Mutation; Colorectal Neoplasms; Colonic Neoplasms
PubMed: 37499275
DOI: 10.1016/j.neo.2023.100918 -
Clinical and Experimental Rheumatology Aug 2023Interstitial lung disease (ILD) has a high prevalence among patients with systemic sclerosis (SSc), carrying high mortality and morbidity. During the last decade, the... (Review)
Review
Interstitial lung disease (ILD) has a high prevalence among patients with systemic sclerosis (SSc), carrying high mortality and morbidity. During the last decade, the emergence of new pharmacological therapies for SSc-associated ILD (SSc-ILD) and improved tools for its diagnosis and monitoring have changed the prevailing clinical approach, highlighting the need for early recognition and prompt treatment for SSc-ILD. Furthermore, the recent approval of multiple therapies for SSc-ILD poses challenges for the rheumatologist and pulmonologist in choosing the appropriate therapy for individual clinical scenarios. We review the pathophysiology of SSc-ILD, and the mechanisms of action and rationale behind current therapies. We also review the evidence of the efficacy and safety of immunosuppressive drugs, antifibrotic agents, and immunomodulators from cyclophosphamide and mycophenolate to novel agents such as nintedanib and tocilizumab. We also emphasise the importance of early diagnosis and monitoring and describe our approach to pharmacological therapy for SSc-ILD patients.
Topics: Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Cyclophosphamide; Scleroderma, Systemic; Patient Care; Lung
PubMed: 37382458
DOI: 10.55563/clinexprheumatol/am4nmv -
Mutation Research. Reviews in Mutation... 2023Error-corrected Next Generation Sequencing (ecNGS) is rapidly emerging as a valuable, highly sensitive and accurate method for detecting and characterizing mutations in... (Review)
Review
Error-corrected Next Generation Sequencing (ecNGS) is rapidly emerging as a valuable, highly sensitive and accurate method for detecting and characterizing mutations in any cell type, tissue or organism from which DNA can be isolated. Recent mutagenicity and carcinogenicity studies have used ecNGS to quantify drug-/chemical-induced mutations and mutational spectra associated with cancer risk. ecNGS has potential applications in genotoxicity assessment as a new readout for traditional models, for mutagenesis studies in 3D organotypic cultures, and for detecting off-target effects of gene editing tools. Additionally, early data suggest that ecNGS can measure clonal expansion of mutations as a mechanism-agnostic early marker of carcinogenic potential and can evaluate mutational load directly in human biomonitoring studies. In this review, we discuss promising applications, challenges, limitations, and key data initiatives needed to enable regulatory testing and adoption of ecNGS - including for advancing safety assessment, augmenting weight-of-evidence for mutagenicity and carcinogenicity mechanisms, identifying early biomarkers of cancer risk, and managing human health risk from chemical exposures.
Topics: Humans; High-Throughput Nucleotide Sequencing; Mutagenicity Tests; Mutation; Mutagens; Carcinogens; Carcinogenesis; Risk Assessment
PubMed: 37643677
DOI: 10.1016/j.mrrev.2023.108466 -
International Journal of Molecular... Dec 2023Genetic diversity is a key factor for plant breeding. The birth of novel genic and genomic variants is also crucial for plant adaptation in nature. Therefore, the... (Review)
Review
Genetic diversity is a key factor for plant breeding. The birth of novel genic and genomic variants is also crucial for plant adaptation in nature. Therefore, the genomes of almost all living organisms possess natural mutagenic mechanisms. Transposable elements (TEs) are a major mutagenic force driving genetic diversity in wild plants and modern crops. The relatively rare TE transposition activity during the thousand-year crop domestication process has led to the phenotypic diversity of many cultivated species. The utilization of TE mutagenesis by artificial and transient acceleration of their activity in a controlled mode is an attractive foundation for a novel type of mutagenesis called TE-mediated biological mutagenesis. Here, I focus on TEs as mutagenic sources for plant breeding and discuss existing and emerging transgene-free approaches for TE activation in plants. Furthermore, I also review the non-randomness of TE insertions in a plant genome and the molecular and epigenetic factors involved in shaping TE insertion preferences. Additionally, I discuss the molecular mechanisms that prevent TE transpositions in germline plant cells (e.g., meiocytes, pollen, egg and embryo cells, and shoot apical meristem), thereby reducing the chances of TE insertion inheritance. Knowledge of these mechanisms can expand the TE activation toolbox using novel gene targeting approaches. Finally, the challenges and future perspectives of plant populations with induced novel TE insertions (iTE plant collections) are discussed.
Topics: Plant Breeding; DNA Transposable Elements; Genome, Plant; Crops, Agricultural; Mutagenesis; Evolution, Molecular
PubMed: 38069377
DOI: 10.3390/ijms242317054 -
Life Sciences Aug 2023The aim of this study is to evaluate the effects of patulin on hepatic lipid metabolism and mitochondrial oxidative function and elucidate the underlying molecular...
AIMS
The aim of this study is to evaluate the effects of patulin on hepatic lipid metabolism and mitochondrial oxidative function and elucidate the underlying molecular mechanisms.
MAIN METHODS
The effects of patulin on hepatic lipid accumulation were evaluated in free fatty acid-treated AML12 or HepG2 cells through oil red O staining, triglyceride assay, real-time polymerase chain reaction, and western blotting. Alteration of mitochondrial oxidative capacity by patulin treatment was determined using Seahorse analysis to measure the oxygen consumption rate.
KEY FINDINGS
The increased amounts of lipid droplets induced by free fatty acids were significantly reduced by patulin treatment. Patulin markedly activated the CaMKII/AMP-activated protein kinase (AMPK)/proliferator-activated receptor-γ coactivator (PGC)-1α signaling pathway in hepatocytes, reduced the expression of sterol regulatory element binding protein 1c (SREBP-1c) and lipogenic genes, and increased the expression of genes related to mitochondrial fatty acid oxidation. In addition, patulin treatment enhanced the mitochondrial consumption rate and increased the expression of mitochondrial oxidative phosphorylation proteins in HepG2 hepatocytes. The effects of patulin on anti-lipid accumulation; SREBP-1c, PGC-1α, and carnitine palmitoyltransferase 1 expression; and mitochondrial oxidative capacity were significantly prevented by compound C, an AMPK inhibitor.
SIGNIFICANCE
Patulin is a potent inducer of the AMPK pathway, and AMPK-mediated mitochondrial activation is required for the efficacy of patulin to inhibit hepatic lipid accumulation. This study is the first to report that patulin is a promising bioactive compound that prevents the development and worsening of fatty liver diseases, including non-alcoholic fatty liver disease, by improving mitochondrial quality and lipid metabolism.
Topics: Humans; Lipogenesis; Patulin; AMP-Activated Protein Kinases; Sterol Regulatory Element Binding Protein 1; Liver; Non-alcoholic Fatty Liver Disease; Lipid Metabolism; Hep G2 Cells; Fatty Acids, Nonesterified; Respiration
PubMed: 37271452
DOI: 10.1016/j.lfs.2023.121816