scholarly journals Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

Oncogene ◽  
2010 ◽  
Vol 30 (12) ◽  
pp. 1489-1496 ◽  
Author(s):  
P Rai ◽  
J J Young ◽  
D G A Burton ◽  
M G Giribaldi ◽  
T T Onder ◽  
...  
Keyword(s):  
Dna Damage ◽  
Guanine Nucleotides ◽  
Premature Senescence ◽  
Oncogenic Ras ◽  
Oxidized Guanine

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 Role of Bacillus subtilis Error Prevention Oxidized Guanine System in Counteracting Hexavalent Chromium-Promoted Oxidative DNA Damage

2014 ◽  
Vol 80 (17) ◽  
pp. 5493-5502 ◽  
Author(s):  
Fernando Santos-Escobar ◽  
J. Félix Gutiérrez-Corona ◽  
Mario Pedraza-Reyes
Keyword(s):  
Dna Damage ◽  
Bacillus Subtilis ◽  
Hexavalent Chromium ◽  
Oxidative Dna Damage ◽  
Chromosomal Dna ◽  
Error Prevention ◽  
Content Type ◽  
Induced Mutagenesis ◽  
Oxidized Guanine ◽  
Life On Earth

ABSTRACTChromium pollution is potentially detrimental to bacterial soil communities, compromising carbon and nitrogen cycles that are essential for life on earth. It has been proposed that intracellular reduction of hexavalent chromium [Cr(VI)] to trivalent chromium [Cr(III)] may cause bacterial death by a mechanism that involves reactive oxygen species (ROS)-induced DNA damage; the molecular basis of the phenomenon was investigated in this work. Here, we report thatBacillus subtiliscells lacking a functional error prevention oxidized guanine (GO) system were significantly more sensitive to Cr(VI) treatment than cells of the wild-type (WT) strain, suggesting that oxidative damage to DNA is involved in the deleterious effects of the oxyanion. In agreement with this suggestion, Cr(VI) dramatically increased the ROS concentration and induced mutagenesis in a GO-deficientB. subtilisstrain. Alkaline gel electrophoresis (AGE) analysis of chromosomal DNA of WT and ΔGO mutant strains subjected to Cr(VI) treatment revealed that the DNA of the ΔGO strain was more susceptible to DNA glycosylase Fpg attack, suggesting that chromium genotoxicity is associated with 7,8-dihydro-8-oxodeoxyguanosine (8-oxo-G) lesions. In support of this notion, specific monoclonal antibodies detected the accumulation of 8-oxo-G lesions in the chromosomes ofB. subtiliscells subjected to Cr(VI) treatment. We conclude that Cr(VI) promotes mutagenesis and cell death inB. subtilisby a mechanism that involves radical oxygen attack of DNA, generating 8-oxo-G, and that such effects are counteracted by the prevention and repair GO system.

scholarly journals DDB2, an Essential Mediator of Premature Senescence

2010 ◽  
Vol 30 (11) ◽  
pp. 2681-2692 ◽  
Author(s):  
Nilotpal Roy ◽  
Tanya Stoyanova ◽  
Carmen Dominguez-Brauer ◽  
Hyun Jung Park ◽  
Srilata Bagchi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Excision Repair ◽  
Culture Shock ◽  
Premature Senescence ◽  
Antioxidant Genes ◽  
Repair Protein ◽  
High Level

ABSTRACT Reactive oxygen species (ROS) is critical for premature senescence, a process significant in tumor suppression and cancer therapy. Here, we reveal a novel function of the nucleotide excision repair protein DDB2 in the accumulation of ROS in a manner that is essential for premature senescence. DDB2-deficient cells fail to undergo premature senescence induced by culture shock, exogenous oxidative stress, oncogenic stress, or DNA damage. These cells do not accumulate ROS following DNA damage. The lack of ROS accumulation in DDB2 deficiency results from high-level expression of the antioxidant genes in vitro and in vivo. DDB2 represses antioxidant genes by recruiting Cul4A and Suv39h and by increasing histone-H3K9 trimethylation. Moreover, expression of DDB2 also is induced by ROS. Together, our results show that, upon oxidative stress, DDB2 functions in a positive feedback loop by repressing the antioxidant genes to cause persistent accumulation of ROS and induce premature senescence.

Premature Senescence in Hematopoietic Stem and Progenitor Cells in Ribosomopathy-Associated Bone Marrow Failure Syndromes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 298-298
Author(s):  
Hengjun Chao ◽  
Johnson M. Liu
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Premature Senescence ◽  
Hematopoietic Stem ◽  
Cycle Arrest ◽  
Bone Marrow Failure Syndromes ◽  
P53 Activation ◽  
Adult Bone

Abstract Introduction: Aged hematopoietic stem cells (HSCs) are known to functionally decline and are prone to development of myeloid malignancies. Recent work has highlighted the twin roles of replication stress and decreased ribosome biogenesis as drivers for the accumulation of DNA damage and senescence. Certain bone marrow failure syndromes, including Shwachman-Diamond syndrome (SDS), Diamond-Blackfan anemia (DBA), and the acquired 5q- syndrome, are characterized by defects in ribosome biogenesis. Furthermore, recent work has suggested a role for p53 activation, through the 5S ribonucleoprotein particle (RNP), in driving cells to senescence following perturbation of ribosome biogenesis. Methods and Results: Here, we have used multiplexing flow cytometry protocols to define, enumerate, and characterize hematopoietic cells of distinct differentiation stages and lineages in 2 DBA cord bloods and 4 adult bone marrows (2 SDS, 1 DBA, and 1 patient with a diminutive somatic deletion of 5q: ages 27, 32, 40, and 30, respectively), as compared with 4 normal cord bloods and 6 normal adult bone marrows. We included a patient with bona fide MDS (diminutive somatic deletion of 5q including RPS14 in a young adult) to compare with the SDS and DBA patients, who do not meet criteria for MDS. Our preliminary results revealed significant defects in the primitive HSC and multipotent progenitor (MPP) compartments in both DBA and SDS. Specifically, we found in DBA and SDS bone marrow and cord blood samples (compared to normal controls): significantly decreased numbers of primitive HSCs (Lin-CD34+CD133+CD38-CD45RA-CD49f+CD90+) and MPPs (Lin-CD34+CD133+CD38-CD45RA-CD49f-CD90-); increased levels of apoptosis and dysregulated proliferation; and G0-1/S cell cycle arrest. We also found significant increases in senescence-associated β-galactosidase staining and G0-1/S cell cycle arrest in Lin-CD34+ and Lin-CD34+CD38-CD133+ subpopulations in all 4 adult patient bone marrows, as compared with normal adult bone marrows processed in identical fashion [see Fig. 1 for representative data from Lin-CD34+CD133+ hematopoietic progenitor cells (HPCs) from one SDS patient]. Foci of the phosphorylated form of the variant histone H2AX (γH2AX) mark DNA damage, and γH2AX staining was similarly increased in comparison to controls (Fig. 1). The mechanism whereby disturbed ribosome biogenesis induces senescence has been suggested as involving 5S RNP-mediated p53 activation. However, our experiments did not demonstrate increased levels of p53 in the SDS patient marrows, as assessed by intracellular staining. Levels of p16, a well known marker of senescence, were markedly increased in the SDS patient samples, when compared to controls. Finally, in the 2 DBA cord bloods analyzed, there was increased senescence-associated β-galactosidase staining but to a lesser degree than in the adult bone marrow samples (as might be expected with temporal progression). Discussion: Taken together, our data suggest that ribosomopathies (which often present in childhood) are disorders of premature senescence. Consequent DNA damage accumulation and decreased repair and compensation may account for the development of MDS and acute myeloid leukemia, disorders seen in young ribosomopathy patients that ordinarily are rare in the general pediatric and young adult population. Disclosures No relevant conflicts of interest to declare.

Premature senescence of mesothelial cells is associated with non-telomeric DNA damage

2007 ◽  
Vol 362 (3) ◽  
pp. 707-711 ◽  
Author(s):  
Krzysztof Ksiazek ◽  
João F. Passos ◽  
Sharon Olijslagers ◽  
Gabriele Saretzki ◽  
Carmen Martin-Ruiz ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mesothelial Cells ◽  
Premature Senescence ◽  
Telomeric Dna

scholarly journals Elimination and Utilization of Oxidized Guanine Nucleotides in the Synthesis of RNA and Its Precursors

2013 ◽  
Vol 288 (12) ◽  
pp. 8128-8135 ◽  
Author(s):  
Takeshi Sekiguchi ◽  
Riyoko Ito ◽  
Hiroshi Hayakawa ◽  
Mutsuo Sekiguchi
Keyword(s):  
Guanine Nucleotides ◽  
Oxidized Guanine

scholarly journals Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells

2008 ◽  
Vol 181 (7) ◽  
pp. 1055-1063 ◽  
Author(s):  
Rajini Mudhasani ◽  
Zhiqing Zhu ◽  
Gyorgy Hutvagner ◽  
Christine M. Eischen ◽  
Stephen Lyle ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mature Mirnas ◽  
Mirna Biogenesis ◽  
Premature Senescence ◽  
Primary Cells ◽  
Embryonic Fibroblasts ◽  
P53 Signaling ◽  
Adult Skin

Dicer, an enzyme involved in microRNA (miRNA) maturation, is required for proper cell differentiation and embryogenesis in mammals. Recent evidence indicates that Dicer and miRNA may also regulate tumorigenesis. To better characterize the role of miRNA in primary cell growth, we generated Dicer-conditional mice. Ablation of Dicer and loss of mature miRNAs in embryonic fibroblasts up-regulated p19Arf and p53 levels, inhibited cell proliferation, and induced a premature senescence phenotype that was also observed in vivo after Dicer ablation in the developing limb and in adult skin. Furthermore, deletion of the Ink4a/Arf or p53 locus could rescue fibroblasts from premature senescence induced by Dicer ablation. Although levels of Ras and Myc oncoproteins appeared unaltered, loss of Dicer resulted in increased DNA damage and p53 activity in these cells. These results reveal that loss of miRNA biogenesis activates a DNA damage checkpoint, up-regulates p19Arf-p53 signaling, and induces senescence in primary cells.

scholarly journals Chronic NF-κB activation delays RasV12-induced premature senescence of human fibroblasts by suppressing the DNA damage checkpoint response

2009 ◽  
Vol 130 (7) ◽  
pp. 409-419 ◽  
Author(s):  
Christina Batsi ◽  
Soultana Markopoulou ◽  
George Vartholomatos ◽  
Ioannis Georgiou ◽  
Panagiotis Kanavaros ◽  
...  
Keyword(s):  
Dna Damage ◽  
Human Fibroblasts ◽  
Dna Damage Checkpoint ◽  
Premature Senescence ◽  
Checkpoint Response
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