scholarly journals Splicing Factor SRSF1 Deficiency in the Liver Triggers NASH-like Pathology via R-Loop Induced DNA Damage and Cell Death

2021 ◽  
Author(s):  
Waqar Arif ◽  
Bhoomika Mathur ◽  
Michael F Saikali ◽  
Ullas V Chembazhi ◽  
Steven M Blue ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Genome Stability ◽  
Rna Binding ◽  
Genotoxic Stress ◽  
Splicing Factor ◽  
Metabolic Derangement ◽  
Mrna Metabolism ◽  
Human Liver Cancer ◽  
Human Liver Cancer Cells

Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine–arginine–rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is primarily mediated by the excessive formation of deleterious RNA–DNA hybrids (R–loops), which induce DNA damage. Combining hepatocyte–specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Lipid accumulation in SRSF1–deficient hepatocytes is followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH–like liver pathology. Importantly, SRSF1–depleted human liver cancer cells recapitulate this pathogenesis illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how accumulation of detrimental R–loops impedes hepatocellular gene expression, triggering metabolic derangement and liver failure.

scholarly journals SOG1 transcription factor promotes the onset of endoreduplication under salinity stress in Arabidopsis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kalyan Mahapatra ◽  
Sujit Roy
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Transcription Factor ◽  
Programmed Cell Death ◽  
Salinity Stress ◽  
Crucial Role ◽  
Genome Stability ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Regulators

AbstractAs like in mammalian system, the DNA damage responsive cell cycle checkpoint functions play crucial role for maintenance of genome stability in plants through repairing of damages in DNA and induction of programmed cell death or endoreduplication by extensive regulation of progression of cell cycle. ATM and ATR (ATAXIA-TELANGIECTASIA-MUTATED and -RAD3-RELATED) function as sensor kinases and play key role in the transmission of DNA damage signals to the downstream components of cell cycle regulatory network. The plant-specific NAC domain family transcription factor SOG1 (SUPPRESSOR OF GAMMA RESPONSE 1) plays crucial role in transducing signals from both ATM and ATR in presence of double strand breaks (DSBs) in the genome and found to play crucial role in the regulation of key genes involved in cell cycle progression, DNA damage repair, endoreduplication and programmed cell death. Here we report that Arabidopsis exposed to high salinity shows generation of oxidative stress induced DSBs along with the concomitant induction of endoreduplication, displaying increased cell size and DNA ploidy level without any change in chromosome number. These responses were significantly prominent in SOG1 overexpression line than wild-type Arabidopsis, while sog1 mutant lines showed much compromised induction of endoreduplication under salinity stress. We have found that both ATM-SOG1 and ATR-SOG1 pathways are involved in the salinity mediated induction of endoreduplication. SOG1was found to promote G2-M phase arrest in Arabidopsis under salinity stress by downregulating the expression of the key cell cycle regulators, including CDKB1;1, CDKB2;1, and CYCB1;1, while upregulating the expression of WEE1 kinase, CCS52A and E2Fa, which act as important regulators for induction of endoreduplication. Our results suggest that Arabidopsis undergoes endoreduplicative cycle in response to salinity induced DSBs, showcasing an adaptive response in plants under salinity stress.

scholarly journals Genome Maintenance Mechanisms at the Chromatin Level

2021 ◽  
Vol 22 (19) ◽  
pp. 10384
Author(s):  
Hirotomo Takatsuka ◽  
Atsushi Shibata ◽  
Masaaki Umeda
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Genotoxic Stress ◽  
Genome Integrity ◽  
Easy Access ◽  
Order Structure ◽  
Chromatin Modifications ◽  
Level Control ◽  
Regulatory Systems

Genome integrity is constantly threatened by internal and external stressors, in both animals and plants. As plants are sessile, a variety of environment stressors can damage their DNA. In the nucleus, DNA twines around histone proteins to form the higher-order structure “chromatin”. Unraveling how chromatin transforms on sensing genotoxic stress is, thus, key to understanding plant strategies to cope with fluctuating environments. In recent years, accumulating evidence in plant research has suggested that chromatin plays a crucial role in protecting DNA from genotoxic stress in three ways: (1) changes in chromatin modifications around damaged sites enhance DNA repair by providing a scaffold and/or easy access to DNA repair machinery; (2) DNA damage triggers genome-wide alterations in chromatin modifications, globally modulating gene expression required for DNA damage response, such as stem cell death, cell-cycle arrest, and an early onset of endoreplication; and (3) condensed chromatin functions as a physical barrier against genotoxic stressors to protect DNA. In this review, we highlight the chromatin-level control of genome stability and compare the regulatory systems in plants and animals to find out unique mechanisms maintaining genome integrity under genotoxic stress.

scholarly journals PARP-1–dependent recruitment of cold-inducible RNA-binding protein promotes double-strand break repair and genome stability

2018 ◽  
Vol 115 (8) ◽  
pp. E1759-E1768 ◽  
Author(s):  
Jung-Kuei Chen ◽  
Wen-Ling Lin ◽  
Zhang Chen ◽  
Hung-wen Liu
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Strand Break ◽  
Double Strand Break ◽  
Dsb Repair ◽  
Active Involvement ◽  
Parp 1

Maintenance of genome integrity is critical for both faithful propagation of genetic information and prevention of mutagenesis induced by various DNA damage events. Here we report cold-inducible RNA-binding protein (CIRBP) as a newly identified key regulator in DNA double-strand break (DSB) repair. On DNA damage, CIRBP temporarily accumulates at the damaged regions and is poly(ADP ribosyl)ated by poly(ADP ribose) polymerase-1 (PARP-1). Its dissociation from the sites of damage may depend on its phosphorylation status as mediated by phosphatidylinositol 3-kinase-related kinases. In the absence of CIRBP, cells showed reduced γH2AX, Rad51, and 53BP1 foci formation. Moreover, CIRBP-depleted cells exhibited impaired homologous recombination, impaired nonhomologous end-joining, increased micronuclei formation, and higher sensitivity to gamma irradiation, demonstrating the active involvement of CIRBP in DSB repair. Furthermore, CIRBP depleted cells exhibited defects in DNA damage-induced chromatin association of the MRN complex (Mre11, Rad50, and NBS1) and ATM kinase. CIRBP depletion also reduced phosphorylation of a variety of ATM substrate proteins and thus impaired the DNA damage response. Taken together, these results reveal a previously unrecognized role for CIRBP in DSB repair.

scholarly journals THE STATE OF THE CELLS OF THE IMMUNE SYSTEM IN EXPERIMENTAL IMMUNE-MEDIATED INFLAMMATION OF VARIOUS GENESIS

2021 ◽  
Vol 17 (2) ◽  
pp. 20-26
Author(s):  
S.I. Pavlovych ◽  
N.G. Grushka ◽  
O.A. Kondratska ◽  
N.O. Krasutska ◽  
R.I. Yanchii
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Membrane Integrity ◽  
Genotoxic Stress ◽  
Pathological Process ◽  
The Body ◽  
Cellular Mechanisms ◽  
Nonspecific Resistance ◽  
Immune Mediated ◽  
Endotoxemia Model

Relevance. Immune-mediated inflammation of various genesis plays a significant pathogenetic role in autoimmune, allergic, inflammatory and infectious diseases. The objective of the work was a comparative study of the functional status and pathways of cell death of natural and adaptive immunity in mice under the conditions of experimental hyperimmunocomplexemia and endotoxemia to identify the features and common cellular mechanisms of these pathologies. Materials and methods. Hyperimmunocomplexemia was simulated by six-fold immunization of female mice with increasing doses of the antigen, bovine serum albumin (BSA), once a week; the endotoxemia model was induced by the administration of lipopolysaccharide (LPS). Results. The use of both BSA and LPS led to a systemic inflammatory process with significant neutrophilia with a shift of the leukogram to the left. There was a significant increase in the functional and metabolic activity of nonspecific resistance cells. Genotoxic stress was observed in thymus cells and lymph nodes with significant DNA damage, decreased viability, and a significant increase in necrotic death. Violation of the plasma membrane integrity of primary alteration and the release of the cellular content outside has a strong pro-inflammatory and immunogenic effect, which can lead to further intensification of the disease and an increase in its duration with a tendency to chronicity of the pathological process. Conclusions. Thus, both models are characterized by the development of immune-inflammatory processes that lead to significant DNA damage and cell death, which can cause a new round of intensification of necrotic, inflammatory and autoimmune reactions in the body.

scholarly journals LARP7 is a BRCA1 ubiquitinase substrate and regulates genome stability and tumorigenesis

2019 ◽  
Author(s):  
Fang Zhang ◽  
Pengyi Yan ◽  
Huijing Yu ◽  
Huangying Le ◽  
Zixuan li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Rna Binding ◽  
Tumor Therapy ◽  
Genotoxic Stress ◽  
Therapy Resistance ◽  
List Type ◽  
M Cell

SummaryAttenuated DNA repair leads to genomic instability and tumorigenesis. BRCA1/BARD1 are the best known tumor suppressors that promote homology recombination (HR) and arrest cell cycle at G2/M checkpoint. As E3 ubiquitin ligases, their ubiquitinase activity has been known to involve in the HR and tumor suppression, but the mechanism remains ambiguous. Here, we demonstrated upon genotoxic stress, BRCA1 together with BARD1 catalyzed the K48 ployubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degraded it through 26S ubiquitin-proteasome pathway. Depleting LARP7 suppressed the expression of CDK1 complex, arrested cell at G2/M DNA damage checkpoint and reduced BRCA2 phosphorylation which thereby facilitated RAD51 recruitment to damaged DNA to enhance HR. Importantly, LARP7 depletion observed in breast patients lead to the chemoradiotherapy resistance both in vitro and in vivo. Together, this study unveils a mechanism by which BRCA1/BARD1 utilizes their E3 ligase activity to control HR and cell cycle, and highlights LARP7 as a potential target for cancer prevention and therapy.HighlightsDNA damage response downregulates LARP7 through BRCA1/BARD1BRCA1/BARD1 catalyzes the K48 polyubiquitination on LARP7LARP7 promotes G2/M cell cycle transition and tumorigenesis via CDK1 complexLARP7 disputes homology-directed repair that leads to tumor therapy resistance

scholarly journals Sam68/KHDRBS1 is critical for colon tumorigenesis by regulating genotoxic stress-induced NF-κB activation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Kai Fu ◽  
Xin Sun ◽  
Eric M Wier ◽  
Andrea Hodgson ◽  
Yue Liu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Dna Damage ◽  
Signaling Pathway ◽  
Rna Binding ◽  
Genotoxic Stress ◽  
Human Colon ◽  
Tumor Burden ◽  
Human Colon Cancer ◽  
Nuclear Signaling ◽  
Colon Tumorigenesis

Nuclear factor kappa B (NF-κB)-mediated transcription is an important mediator for cellular responses to DNA damage. Genotoxic agents trigger a 'nuclear-to-cytoplasmic' NF-κB activation signaling pathway; however, the early nuclear signaling cascade linking DNA damage and NF-κB activation is poorly understood. Here we report that Src-associated-substrate-during-mitosis-of-68kDa/KH domain containing, RNA binding, signal transduction associated 1 (Sam68/KHDRBS1) is a key NF-κB regulator in genotoxic stress-initiated signaling pathway. Sam68 deficiency abolishes DNA damage-stimulated polymers of ADP-ribose (PAR) production and the PAR-dependent NF-κB transactivation of anti-apoptotic genes. Sam68 deleted cells are hypersensitive to genotoxicity caused by DNA damaging agents. Upregulated Sam68 coincides with elevated PAR production and NF-κB-mediated anti-apoptotic transcription in human and mouse colon cancer. Knockdown of Sam68 sensitizes human colon cancer cells to genotoxic stress-induced apoptosis and genetic deletion of Sam68 dampens colon tumor burden in mice. Together our data reveal a novel function of Sam68 in the genotoxic stress-initiated nuclear signaling, which is crucial for colon tumorigenesis.

scholarly journals Selective aggregation of the splicing factor Hsh155 suppresses splicing upon genotoxic stress

2017 ◽  
Vol 216 (12) ◽  
pp. 4027-4040 ◽  
Author(s):  
Veena Mathew ◽  
Annie S. Tam ◽  
Karissa L. Milbury ◽  
Analise K. Hofmann ◽  
Christopher S. Hughes ◽  
...  
Keyword(s):  
Genome Stability ◽  
Protein Quality ◽  
Intron Retention ◽  
Ribosomal Protein Gene ◽  
Genotoxic Stress ◽  
Splicing Factor ◽  
Stress Recovery ◽  
Gene Transcripts ◽  
Splicing Efficiency ◽  
Selective Aggregation

Upon genotoxic stress, dynamic relocalization events control DNA repair as well as alterations of the transcriptome and proteome, enabling stress recovery. How these events may influence one another is only partly known. Beginning with a cytological screen of genome stability proteins, we find that the splicing factor Hsh155 disassembles from its partners and localizes to both intranuclear and cytoplasmic protein quality control (PQC) aggregates under alkylation stress. Aggregate sequestration of Hsh155 occurs at nuclear and then cytoplasmic sites in a manner that is regulated by molecular chaperones and requires TORC1 activity signaling through the Sfp1 transcription factor. This dynamic behavior is associated with intron retention in ribosomal protein gene transcripts, a decrease in splicing efficiency, and more rapid recovery from stress. Collectively, our analyses suggest a model in which some proteins evicted from chromatin and undergoing transcriptional remodeling during stress are targeted to PQC sites to influence gene expression changes and facilitate stress recovery.

scholarly journals The MAPK Pathway Signals Telomerase Modulation in Response to Isothiocyanate-Induced DNA Damage of Human Liver Cancer Cells

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e53240 ◽  
Author(s):  
Evelyn Lamy ◽  
Corinna Herz ◽  
Sabine Lutz-Bonengel ◽  
Anke Hertrampf ◽  
Melinda-Rita Márton ◽  
...  
Keyword(s):  
Dna Damage ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Human Liver ◽  
Mapk Pathway ◽  
Liver Cancer Cells ◽  
Human Liver Cancer ◽  
Human Liver Cancer Cells

scholarly journals Plasmodium falciparum Replication factor C subunit 1 is involved in genotoxic stress response

2020 ◽  
Author(s):  
O Sheriff ◽  
Y Aniweh ◽  
Soak-Kuan Lai ◽  
HL Loo ◽  
S. K Sze ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Plasmodium Falciparum ◽  
Stress Response ◽  
Programmed Cell Death ◽  
Genotoxic Stress ◽  
Antimalarial Drugs ◽  
Protein Levels ◽  
Factor C

AbstractAbout half the world’s population is at risk of malaria, with Plasmodium falciparum malaria being responsible for the most malaria related deaths globally. Antimalarial drugs such as chloroquine and artemisinin are directed towards the proliferating intra-erythrocytic stages of the parasite, which is responsible for all the clinical symptoms of the disease. These antimalarial drugs have been reported to function via multiple pathways, one of which induces DNA damage via the generation of free radicals and reactive oxygen species. An urgent need to understand the mechanistic details of drug response and resistance is highlighted by the decreasing clinical efficacy of the front line drug, Artemisinin.The replication factor C subunit 1 protein is an important component of the DNA replication machinery and DNA damage response mechanism. Here we show the translocation of PfRFC1 from an intranuclear localization to the nuclear periphery indicating an orchestrated progression of distinct patterns of replication in the developing parasites. PfRFC1 responds to genotoxic stress via elevated protein levels in soluble and chromatin bound fractions.Reduction of PfRFC1 protein levels upon treatment with antimalarials suggests an interplay of replication and DNA repair pathways leading to cell death. Additionally, mislocalization of the endogenously tagged protein confirmed its essential role in parasites’ replication and DNA repair. This study provides key insights into DNA replication, DNA damage response and cell death in plasmodium falciparum.ImportanceFrontline drugs have been found to induce DNA damage in the human malaria parasite Plasmodium falciparum. The genotoxic stress response in Plasmodium and the interplay between DNA damage repair, replication and activation of programmed cell death pathways remains largely undescribed. This study shows a distinct pattern of localization of PfRFC1 during replication and DNA repair. PfRFC1 responds to genotoxic stress with an increase in protein expression. Interfering with the RFC complex formation or mislocalization of PfRFC1 is associated with disrupted genotoxic stress response. Additionally, a reduction of PfRFC1 protein levels is observed upon treatment with antimalarial drugs or under apoptosis like conditions, highlighting the role of DEVD/G like motif in mediating programmed cell death in these parasites. This study sheds light on the role of PfRFC1 in differentially responding to replication, genotoxic stress and programmed cell death in Plasmodium parasites.

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