scholarly journals BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss

2013 ◽  
Vol 33 (9) ◽  
pp. 1819-1829 ◽  
Author(s):  
Zhigang Tu ◽  
Xinying Zhuang ◽  
Yong-Gang Yao ◽  
Rugang Zhang
Keyword(s):  
Dna Damage ◽  
Molecular Mechanism ◽  
Chromatin Remodeling ◽  
Cellular Senescence ◽  
Chromatin Immunoprecipitation ◽  
Tumor Suppression ◽  
Gene Promoters ◽  
Independent Manner ◽  
Oncogenic Ras ◽  
Suppression Mechanism

Cellular senescence is an important tumor suppression mechanism. We have previously reported that both oncogene-induced dissociation of BRCA1 from chromatin and BRCA1 knockdown itself drive senescence by promoting formation of s enescence- a ssociated h eterochromatin f oci (SAHF). However, the molecular mechanism by which BRCA1 regulates SAHF formation and senescence is unclear. BRG1 is a chromatin-remodeling factor that interacts with BRCA1 and pRB. Here we show that BRG1 is required for SAHF formation and senescence induced by oncogenic RAS or BRCA1 loss. The interaction between BRG1 and BRCA1 is disrupted during senescence. This correlates with an increased level of chromatin-associated BRG1 in senescent cells. BRG1 knockdown suppresses the formation of SAHF and senescence, while it has no effect on BRCA1 chromatin dissociation induced by oncogenic RAS, indicating that BRG1 functions downstream of BRCA1 chromatin dissociation. Furthermore, BRG1 knockdown inhibits SAHF formation and senescence induced by BRCA1 knockdown. Conversely, BRG1 overexpression drives SAHF formation and senescence in a DNA damage-independent manner. This effect depends upon BRG1's chromatin-remodeling activity as well as the interaction between BRG1 and pRB. Indeed, the interaction between BRG1 and pRB is enhanced during senescence. Chromatin immunoprecipitation analysis revealed that BRG1's association with the human CDKN2A and CDKN1A gene promoters was enhanced during senescence induced by oncogenic RAS or BRCA1 knockdown. Consistently, knockdown of pRB, p21 CIP1 , and p16 INK4a , but not p53, suppressed SAHF formation induced by BRG1. Together, these studies reveal the molecular underpinning by which BRG1 acts downstream of BRCA1 to promote SAHF formation and senescence.

scholarly journals Molecular basis of chromatin remodeling by Rhp26, a yeast CSB ortholog

2019 ◽  
Vol 116 (13) ◽  
pp. 6120-6129 ◽  
Author(s):  
Wei Wang ◽  
Jun Xu ◽  
Oliver Limbo ◽  
Jia Fei ◽  
George A. Kassavetis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Molecular Mechanism ◽  
Chromatin Remodeling ◽  
Molecular Basis ◽  
Dna Damage Repair ◽  
Genome Integrity ◽  
Chromatin Remodelers ◽  
Free Dna ◽  
Damage Repair

CSB/ERCC6 belongs to an orphan subfamily of SWI2/SNF2-related chromatin remodelers and plays crucial roles in gene expression, DNA damage repair, and the maintenance of genome integrity. The molecular basis of chromatin remodeling by Cockayne syndrome B protein (CSB) is not well understood. Here we investigate the molecular mechanism of chromatin remodeling by Rhp26, aSchizosaccharomyces pombeCSB ortholog. The molecular basis of chromatin remodeling and nucleosomal epitope recognition by Rhp26 is distinct from that of canonical chromatin remodelers, such as imitation switch protein (ISWI). We reveal that the remodeling activities are bidirectionally regulated by CSB-specific motifs: the N-terminal leucine-latch motif and the C-terminal coupling motif. Rhp26 remodeling activities depend mainly on H4 tails and to a lesser extent on H3 tails, but not on H2A and H2B tails. Rhp26 promotes the disruption of histone cores and the release of free DNA. Finally, we dissected the distinct contributions of two Rhp26 C-terminal regions to chromatin remodeling and DNA damage repair.

scholarly journals Nucleosome remodelling at origins of Global Genome-Nucleotide Excision Repair occurs at the boundaries of higher-order chromatin structure

2018 ◽  
Author(s):  
Patrick van Eijk ◽  
Shuvro Prokash Nandi ◽  
Shirong Yu ◽  
Mark Bennett ◽  
Matthew Leadbitter ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nucleotide Excision Repair ◽  
Chromatin Remodeling ◽  
Excision Repair ◽  
Linear Structure ◽  
Higher Order ◽  
Open Reading Frames ◽  
Specific Gene ◽  
Gene Promoters ◽  
Nucleotide Excision

AbstractRepair of UV-induced DNA damage requires chromatin remodeling. How repair is initiated in chromatin remains largely unknown. We recently demonstrated that Global Genome Nucleotide Excision Repair (GG-NER) in chromatin is organized into domains around open reading frames. Here, we identify these domains, and by examining DNA damage-induced changes in the linear structure of nucleosomes, we demonstrate how chromatin remodeling is initiated during repair. In undamaged cells, we show that the GG-NER complex occupies chromatin at nucleosome free regions of specific gene promoters. This establishes the nucleosome structure at these genomic locations, which we refer to as GG-NER complex binding sites (GCBS’s). We demonstrate that these sites are frequently located at genomic boundaries that delineate chromasomally interacting domains (CIDs). These boundaries define domains of higher-order nucleosome-nucleosome interaction. We show that efficient repair of DNA damage in chromatin is initiated following disruption of H2A.Z-containing nucleosomes adjacent to GCBSs by the GG-NER complex.

scholarly journals Actin-Related Protein 6 (Arp6) Influences Double-Strand Break Repair in Yeast

2021 ◽  
Vol 1 (2) ◽  
pp. 225-238
Author(s):  
Mohsen Hooshyar ◽  
Daniel Burnside ◽  
Maryam Hajikarimlou ◽  
Katayoun Omidi ◽  
Alexander Jesso ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromatin Remodeling ◽  
Genetic Interaction ◽  
Interaction Analysis ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Dna Damaging Agents ◽  
Repair Efficiency ◽  
Chromosomal Breaks

DNA double-strand breaks (DSBs) are the most deleterious form of DNA damage and are repaired through non-homologous end-joining (NHEJ) or homologous recombination (HR). Repair initiation, regulation and communication with signaling pathways require several histone-modifying and chromatin-remodeling complexes. In budding yeast, this involves three primary complexes: INO80-C, which is primarily associated with HR, SWR1-C, which promotes NHEJ, and RSC-C, which is involved in both pathways as well as the general DNA damage response. Here we identify ARP6 as a factor involved in DSB repair through an RSC-C-related pathway. The loss of ARP6 significantly reduces the NHEJ repair efficiency of linearized plasmids with cohesive ends, impairs the repair of chromosomal breaks, and sensitizes cells to DNA-damaging agents. Genetic interaction analysis indicates that ARP6, MRE11 and RSC-C function within the same pathway, and the overexpression of ARP6 rescues rsc2∆ and mre11∆ sensitivity to DNA-damaging agents. Double mutants of ARP6, and members of the INO80 and SWR1 complexes, cause a significant reduction in repair efficiency, suggesting that ARP6 functions independently of SWR1-C and INO80-C. These findings support a novel role for ARP6 in DSB repair that is independent of the SWR1 chromatin remodeling complex, through an apparent RSC-C and MRE11-associated DNA repair pathway.

scholarly journals iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Delin Chen ◽  
Bo Chu ◽  
Xin Yang ◽  
Zhaoqi Liu ◽  
Ying Jin ◽  
...  
Keyword(s):  
Tumor Suppression ◽  
Normal Development ◽  
Oxygen Species ◽  
Glycerol Backbone ◽  
Independent Manner ◽  
Obvious Effect ◽  
Normal Tissues ◽  
Induced Stress ◽  
Promising Therapeutic Target ◽  
Oxidized Fatty Acids

AbstractHere, we identify iPLA2β as a critical regulator for p53-driven ferroptosis upon reactive oxygen species (ROS)-induced stress. The calcium-independent phospholipase iPLA2β is known to cleave acyl tails from the glycerol backbone of lipids and release oxidized fatty acids from phospholipids. We found that iPLA2β-mediated detoxification of peroxidized lipids is sufficient to suppress p53-driven ferroptosis upon ROS-induced stress, even in GPX4-null cells. Moreover, iPLA2β is overexpressed in human cancers; inhibition of endogenous iPLA2β sensitizes tumor cells to p53-driven ferroptosis and promotes p53-dependent tumor suppression in xenograft mouse models. These results demonstrate that iPLA2β acts as a major ferroptosis repressor in a GPX4-independent manner. Notably, unlike GPX4, loss of iPLA2β has no obvious effect on normal development or cell viability in normal tissues but iPLA2β plays an essential role in regulating ferroptosis upon ROS-induced stress. Thus, our study suggests that iPLA2β is a promising therapeutic target for activating ferroptosis-mediated tumor suppression without serious toxicity concerns.

scholarly journals Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Patrick D. Rädler ◽  
Barbara L. Wehde ◽  
Aleata A. Triplett ◽  
Hridaya Shrestha ◽  
Jonathan H. Shepherd ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Epithelial Cells ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Ras Signaling ◽  
Preneoplastic Lesions ◽  
Independent Manner ◽  
Oncogenic Ras ◽  
Luminal Epithelial Cells

AbstractClaudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.

scholarly journals CDC25B induces cellular senescence and correlates with tumor suppression in a p53-dependent manner

2021 ◽  
pp. 100564
Author(s):  
Ying-Chieh Chen ◽  
Hsi-Hsien Hsieh ◽  
Hsi-Chi Chang ◽  
Hsin-Chiao Wang ◽  
Wey-Jinq Lin ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Tumor Suppression ◽  
Dependent Manner

scholarly journals Replication stress-induced endogenous DNA damage drives cellular senescence induced by a sub-lethal oxidative stress

2017 ◽  
Vol 45 (18) ◽  
pp. 10564-10582 ◽  
Author(s):  
Gireedhar Venkatachalam ◽  
Uttam Surana ◽  
Marie-Véronique Clément
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cellular Senescence ◽  
Replication Stress

Characterization of DNA damage-induced cellular senescence by ionizing radiation in endothelial cells

2013 ◽  
Vol 90 (1) ◽  
pp. 71-80 ◽  
Author(s):  
Kwang Seok Kim ◽  
Jung Eun Kim ◽  
Kyu Jin Choi ◽  
Sangwoo Bae ◽  
Dong Ho Kim
Keyword(s):  
Dna Damage ◽  
Endothelial Cells ◽  
Ionizing Radiation ◽  
Cellular Senescence
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