Functions of SMC2 in the Development of Zebrafish Liver

SMC2 (structural maintenance of chromosomes 2) is the core subunit of condensins, which play a central role in chromosome organization and segregation. However, the functions of SMC2 in embryonic development remain poorly understood, due to the embryonic lethality of homozygous SMC2−/− mice. Herein, we explored the roles of SMC2 in the liver development of zebrafish. The depletion of SMC2, with the CRISPR/Cas9-dependent gene knockout approach, led to a small liver phenotype. The specification of hepatoblasts was unaffected. Mechanistically, extensive apoptosis occurred in the liver of SMC2 mutants, which was mainly associated with the activation of the p53-dependent apoptotic pathway. Moreover, an aberrant activation of a series of apoptotic pathways in SMC2 mutants was involved in the defective chromosome segregation and subsequent DNA damage. Therefore, our findings demonstrate that SMC2 is necessary for zebrafish liver development.

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Apoptosis mediated chemosensitization of tumor cells to 5-fluorouracil on supplementation of fish oil in experimental colon carcinoma

Tumor Biology ◽

10.1177/1010428317695019 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769501 ◽

Cited By ~ 10

Author(s):

Isha Rani ◽

Bhoomika Sharma ◽

Sandeep Kumar ◽

Satinder Kaur ◽

Navneet Agnihotri

Keyword(s):

Fatty Acids ◽

Dna Damage ◽

Polyunsaturated Fatty Acids ◽

Fish Oil ◽

Tumor Cells ◽

Apoptotic Index ◽

Apoptotic Pathway ◽

Apoptotic Effect ◽

Underlying Mechanisms ◽

Apoptotic Pathways

5-Fluorouracil has been considered as a cornerstone therapy for colorectal cancer; however, it suffers from low therapeutic response rate and severe side effects. Therefore, there is an urgent need to increase the clinical efficacy of 5-fluorouracil. Recently, fish oil rich in n-3 polyunsaturated fatty acids has been reported to chemosensitize tumor cells to anti-cancer drugs. This study is designed to understand the underlying mechanisms of synergistic effect of fish oil and 5-fluorouracil by evaluation of tumor cell–associated markers such as apoptosis and DNA damage. The colon cancer was developed by administration of N,N-dimethylhydrazine dihydrochloride and dextran sulfate sodium salt. Further these animals were treated with 5-fluorouracil, fish oil, or a combination of both. In carcinogen-treated animals, a decrease in DNA damage and apoptotic index was observed. There was also a decrease in the expression of Fas, FasL, caspase 8, and Bax, and an increase in Bcl-2. In contrast, administration of 5-fluorouracil and fish oil as an adjuvant increased both DNA damage and apoptotic index by activation of both extrinsic and intrinsic apoptotic pathways as compared to the other groups. The increased pro-apoptotic effect by synergism of 5-fluorouracil and fish oil may be attributed to the incorporation of n-3 polyunsaturated fatty acids in membrane, which alters membrane fluidity in cancer cells. In conclusion, this study highlights that the induction of apoptotic pathway by fish oil may increase the susceptibility of tumors to chemotherapeutic regimens.

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Deciphering the Enigma of the Histone H2A.Z-1/H2A.Z-2 Isoforms: Novel Insights and Remaining Questions

Cells ◽

10.3390/cells9051167 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1167

Author(s):

Manjinder S. Cheema ◽

Katrina V. Good ◽

Bohyun Kim ◽

Heddy Soufari ◽

Connor O’Sullivan ◽

...

Keyword(s):

Gene Expression ◽

Amino Acids ◽

Dna Damage ◽

Chromosome Segregation ◽

Multiple Roles ◽

Histone H2a ◽

The Core ◽

Structural Differences ◽

Functional Involvement ◽

Insight Into

The replication independent (RI) histone H2A.Z is one of the more extensively studied variant members of the core histone H2A family, which consists of many replication dependent (RD) members. The protein has been shown to be indispensable for survival, and involved in multiple roles from DNA damage to chromosome segregation, replication, and transcription. However, its functional involvement in gene expression is controversial. Moreover, the variant in several groups of metazoan organisms consists of two main isoforms (H2A.Z-1 and H2A.Z-2) that differ in a few (3–6) amino acids. They comprise the main topic of this review, starting from the events that led to their identification, what is currently known about them, followed by further experimental, structural, and functional insight into their roles. Despite their structural differences, a direct correlation to their functional variability remains enigmatic. As all of this is being elucidated, it appears that a strong functional involvement of isoform variability may be connected to development.

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Nucleoporin 62-Like Protein is Required for the Development of Pharyngeal Arches through Regulation of Wnt/β-Catenin Signaling and Apoptotic Homeostasis in Zebrafish

Cells ◽

10.3390/cells8091038 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1038 ◽

Cited By ~ 1

Author(s):

Yang ◽

Li ◽

Gu ◽

Li ◽

Cui

Keyword(s):

Chondrogenic Differentiation ◽

Gene Knockout ◽

Significant Loss ◽

Apoptotic Pathway ◽

Pharyngeal Arches ◽

Pharyngeal Region ◽

And Migration ◽

Apoptotic Pathways ◽

Cranial Neural Crest Cells ◽

Predominant Expression

We have previously observed the predominant expression of nucleoporin 62-like (Nup62l) mRNA in the pharyngeal region of zebrafish, which raises the question whether Nup62l has important implications in governing the morphogenesis of pharyngeal arches (PA) in zebrafish. Herein, we explored the functions of Nup62l in PA development. The disruption of Nup62l with a CRISPR/Cas9-dependent gene knockout approach led to defective PA, which was characterized by a thinned and shortened pharyngeal region and a significant loss of pharyngeal cartilages. During pharyngeal cartilage formation, prechondrogenic condensation and chondrogenic differentiation were disrupted in homozygous nup62l-mutants, while the specification and migration of cranial neural crest cells (CNCCs) were unaffected. Mechanistically, the impaired PA region of nup62l-mutants underwent extensive apoptosis, which was mainly dependent on activation of p53-dependent apoptotic pathway. Moreover, aberrant activation of a series of apoptotic pathways in nup62l-mutants is closely associated with the inactivation of Wnt/β-catenin signaling. Thus, these findings suggest that the regulation of Wnt/β-catenin activity by Nup62l is crucial for PA formation in zebrafish.

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A Mycobacterial smc Null Mutant Is Proficient in DNA Repair and Long-Term Survival

Journal of Bacteriology ◽

10.1128/jb.01315-07 ◽

2007 ◽

Vol 190 (1) ◽

pp. 452-456 ◽

Cited By ~ 15

Author(s):

Carolin Güthlein ◽

Roger M. Wanner ◽

Peter Sander ◽

Erik C. Böttger ◽

Burkhard Springer

Keyword(s):

Dna Damage ◽

Mycobacterium Tuberculosis ◽

Mycobacterium Smegmatis ◽

Chromosome Organization ◽

Null Mutant ◽

Term Survival ◽

Mutant Strains ◽

Structural Maintenance Of Chromosomes ◽

Null Mutants

ABSTRACT SMC (structural maintenance of chromosomes) proteins play fundamental roles in various aspects of chromosome organization and dynamics, including repair of DNA damage. Mutant strains of Mycobacterium smegmatis and Mycobacterium tuberculosis defective in SMC were constructed. Surprisingly, inactivation of smc did not result in recognizable phenotypes in hallmark assays characteristic for the function of these genes. This is in contrast to data for smc null mutants in other species.

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The SMC complex, MukBEF, organizes the Escherichia coli chromosome by forming an axial core

10.1101/696872 ◽

2019 ◽

Author(s):

Jarno Mäkelä ◽

David J. Sherratt

Keyword(s):

Escherichia Coli ◽

Replication Origin ◽

Quantitative Imaging ◽

Chromosome Organization ◽

Chromosomal Dna ◽

E Coli ◽

The Core ◽

Structural Maintenance Of Chromosomes ◽

In Cells

AbstractStructural Maintenance of Chromosomes (SMC) complexes organize and individualize chromosomes ubiquitously, thereby contributing to their faithful segregation. Here we explore how Escherichia coli chromosome organization emerges from the action of the SMC complex MukBEF, using quantitative imaging in cells with increased MukBEF occupancy on the chromosome. We demonstrate that the E. coli chromosome is organized as series of loops around a thin axial MukBEF core whose length is ~1100 times shorter than the chromosomal DNA. The core is linear (1 μm), or circular (1.5 μm) in the absence of MatP, which displaces MukBEF from the 800 kbp replication termination region (ter). Our findings illustrate how MukBEF compacts the chromosome lengthwise and demonstrate how displacement of MukBEF from ter promotes MukBEF enrichment with the replication origin.

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Potential Biomarkers for Treatment Response to the BCL-2 Inhibitor Venetoclax: State of the Art and Future Directions

Cancers ◽

10.3390/cancers13122974 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2974

Author(s):

Haneen T. Salah ◽

Courtney D. DiNardo ◽

Marina Konopleva ◽

Joseph D. Khoury

Keyword(s):

Treatment Response ◽

Gene Mutations ◽

Hematologic Malignancies ◽

Mechanisms Of Resistance ◽

Apoptotic Pathway ◽

Lymphoid Leukemia ◽

Optimal Drug ◽

Trisomy 12 ◽

Apoptotic Pathways ◽

Potential Biomarkers

Intrinsic apoptotic pathway dysregulation plays an essential role in all cancers, particularly hematologic malignancies. This role has led to the development of multiple therapeutic agents targeting this pathway. Venetoclax is a selective BCL-2 inhibitor that has been approved for the treatment of chronic lymphoid leukemia and acute myeloid leukemia. Given the reported resistance to venetoclax, understanding the mechanisms of resistance and the potential biomarkers of response is crucial to ensure optimal drug usage and improved patient outcomes. Mechanisms of resistance to venetoclax include alterations involving the BH3-binding groove, BCL2 gene mutations affecting venetoclax binding, and activation of alternative anti-apoptotic pathways. Moreover, various potential genetic biomarkers of venetoclax resistance have been proposed, including chromosome 17p deletion, trisomy 12, and TP53 loss or mutation. This manuscript provides an overview of biomarkers that could predict treatment response to venetoclax.

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Quantitative Profiling of DNA Damage and Apoptotic Pathways in UV Damaged Cells Using PTMScan Direct

International Journal of Molecular Sciences ◽

10.3390/ijms14010286 ◽

2012 ◽

Vol 14 (1) ◽

pp. 286-307 ◽

Cited By ~ 12

Author(s):

Matthew Stokes ◽

Jeffrey Silva ◽

Xiaoying Jia ◽

Kimberly Lee ◽

Roberto Polakiewicz ◽

...

Keyword(s):

Dna Damage ◽

Apoptotic Pathways ◽

Quantitative Profiling

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Mesenchymal stem cells attenuate liver fibrosis by targeting Ly6Chi/lo macrophages through activating the cytokine-paracrine and apoptotic pathways

Cell Death Discovery ◽

10.1038/s41420-021-00584-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yuan-hui Li ◽

Shuang Shen ◽

Tong Shao ◽

Meng-ting Jin ◽

Dong-dong Fan ◽

...

Keyword(s):

Liver Fibrosis ◽

Molecular Mechanisms ◽

Stellate Cell ◽

Apoptotic Bodies ◽

Chronic Injury ◽

Apoptotic Pathway ◽

Fibrotic Liver ◽

Apoptotic Pathways ◽

Regulatory Functions ◽

Cell Inhibition

AbstractMesenchymal stem cell (MSC) therapy has become a promising treatment for liver fibrosis due to its predominant immunomodulatory performance in hepatic stellate cell inhibition and fibrosis resolution. However, the cellular and molecular mechanisms underlying these processes remain limited. In the present study, we provide insights into the functional role of bone marrow-derived MSCs (BM-MSCs) in alleviating liver fibrosis by targeting intrahepatic Ly6Chi and Ly6Clo macrophage subsets in a mouse model. Upon chronic injury, the Ly6Chi subset was significantly increased in the inflamed liver. Transplantation of BM-MSCs markedly promoted a phenotypic switch from pro-fibrotic Ly6Chi subset to restorative Ly6Clo subpopulation by secreting paracrine cytokines IL-4 and IL-10 from the BM-MSCs. The Ly6Chi/Ly6Clo subset switch significantly blocked the source of fibrogenic TGF-β, PDGF, TNF-α, and IL-1β cytokines from Ly6Chi macrophages. Unexpectedly, BM-MSCs experienced severe apoptosis and produced substantial apoptotic bodies in the fibrotic liver during the 72 h period of transplantation. Most apoptotic bodies were engulfed by Ly6Clo macrophages, and this engulfment robustly triggered MMP12 expression for fibrosis resolution through the PtdSer-MerTK-ERK signaling pathway. This paper is the first to show previously unrecognized dual regulatory functions of BM-MSCs in attenuating hepatic fibrosis by promoting Ly6Chi/Ly6Clo subset conversion and Ly6Clo macrophage restoration through secreting antifibrogenic-cytokines and activating the apoptotic pathway.

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Srs2 helicase prevents the formation of toxic DNA damage during late prophase I of yeast meiosis

10.1101/518035 ◽

2019 ◽

Cited By ~ 2

Author(s):

Hiroyuki Sasanuma ◽

Hana Subhan M. Sakurai ◽

Yuko Furihata ◽

Kiran Challa ◽

Lira Palmer ◽

...

Keyword(s):

Dna Damage ◽

Chromosome Segregation ◽

Dna Recombination ◽

Dna Helicase ◽

Aggregate Formation ◽

Late Prophase ◽

Prophase I ◽

Early Protein ◽

Srs2 Helicase ◽

Yeast Meiosis

AbstractProper repair of double-strand breaks (DSBs) is key to ensure proper chromosome segregation. In this study, we found that the deletion of the SRS2 gene, which encodes a DNA helicase necessary for the control of homologous recombination, induces aberrant chromosome segregation during budding yeast meiosis. This abnormal chromosome segregation in srs2 cells accompanies the formation of a novel DNA damage induced during late meiotic prophase-I. The damage may contain long stretches of single-stranded DNAs (ssDNAs), which lead to aggregate formation of a ssDNA binding protein, RPA, and a RecA homolog, Rad51, as well as other recombination proteins inside of the nuclei. The Rad51 aggregate formation in the srs2 mutant depends on the initiation of meiotic recombination and occurs in the absence of chromosome segregation. Importantly, as an early recombination intermediate, we detected a thin bridge of Rad51 between two Rad51 foci or among the foci in the srs2 mutant, which is rarely seen in wild type. These might be cytological manifestation of the connection of two DSB ends and multi-invasion. The DNA damage with Rad51 aggregates in the srs2 mutant is passed through anaphase-I and -II, suggesting the absence of DNA damage-induced cell-cycle arrest after the pachytene stage. We propose that Srs2 helicase resolves early protein-DNA recombination intermediates to suppress the formation of aberrant lethal DNA damage during late prophase-I.

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