scholarly journals DNA damage contributes to age-associated differences in SARS-CoV-2 infection

2021 ◽  
Author(s):  
Rui Jin ◽  
Chang Niu ◽  
Fengyun Wu ◽  
Sixin Zhou ◽  
Tao Han ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genotoxic Stress ◽  
Repair Capacity ◽  
Telomere Attrition ◽  
Dna Repair Capacity ◽  
Activation Of Transcription ◽  
Novel Target ◽  
Factor C

Abstract Coronavirus disease 2019 (COVID-19), caused by coronavirus SARS-CoV-2, is known to disproportionately affect older individuals1,2. How aging processes affect the disease progression remains largely unknown. Here we found that DNA damage, one of the major causes of aging3, promoted susceptibility to SARS-CoV-2 infection in cells and intestinal organoids. SARS-CoV-2 entry was facilitated by DNA damage caused by telomere attrition or extrinsic genotoxic stress and hampered by inhibition of DNA damage response (DDR). Mechanistic analysis revealed that DDR increased expression of ACE2, the receptor of SARS-CoV-2, by activation of transcription factor c-Jun in vitro and in vivo. Expression of ACE2 was elevated in the older tissues and positively correlated with γH2Ax and phosphorylated c-Jun (p-c-Jun). Finally, targeting DNA damage by increasing the DNA repair capacity, alleviated cell susceptibility to SARS-CoV-2. Our data provide insights into the age-associated differences in SARS-CoV-2 infection and a novel target for anti-viral intervention.

scholarly journals Increased WIP1 Expression With Aging Suppresses the Capacity of Oocytes to Respond to and Repair DNA Damage

2021 ◽  
Vol 9 ◽  
Author(s):  
Jiyeon Leem ◽  
Guang-Yu Bai ◽  
Jae-Sung Kim ◽  
Jeong Su Oh
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Oocyte Quality ◽  
Developmental Competence ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Age Related ◽  
Postovulatory Aging

If fertilization does not occur for a prolonged time after ovulation, oocytes undergo a time-dependent deterioration in quality in vivo and in vitro, referred to as postovulatory aging. The DNA damage response is thought to decline with aging, but little is known about how mammalian oocytes respond to the DNA damage during in vitro postovulatory aging. Here we show that increased WIP1 during in vitro postovulatory aging suppresses the capacity of oocytes to respond to and repair DNA damage. During in vitro aging, oocytes progressively lost their capacity to respond to DNA double-strand breaks, which corresponded with an increase in WIP1 expression. Increased WIP1 impaired the amplification of γ-H2AX signaling, which reduced the DNA repair capacity. WIP1 inhibition restored the DNA repair capacity, which prevented deterioration in oocyte quality and improved the fertilization and developmental competence of aged oocytes. Importantly, WIP1 was also found to be high in maternally aged oocytes, and WIP1 inhibition enhanced the DNA repair capacity of maternally aged oocytes. Therefore, our results demonstrate that increased WIP1 is responsible for the age-related decline in DNA repair capacity in oocytes, and WIP1 inhibition could restore DNA repair capacity in aged oocytes.

Deacetylation Induced Nuclear Condensation of HP1γ Promotes Multiple Myeloma Drug Resistance

2021 ◽  
Author(s):  
Zhiqiang Liu ◽  
Xin Li ◽  
Sheng Wang ◽  
Ying Xie ◽  
Hongmei Jiang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Drug Resistance ◽  
Heterochromatin Protein 1 ◽  
Nuclear Condensation ◽  
Repair Capacity ◽  
Acquired Drug Resistance ◽  
Histone Deacetylase 1

Abstract Acquired chemoresistance to proteasome inhibitors (PIs) is a major obstacle that results in failure to manage patients with multiple myeloma (MM) in the clinic; however, the key regulators and underlying mechanisms are still unclear. In this study, we found that high levels of a chromosomal modifier, heterochromatin protein 1 gamma (HP1γ), are accompanied by a low acetylation level in bortezomib-resistant (BR) MM cells, and aberrant DNA repair capacity is correlated with HP1γ overexpression. Mechanistically, the deacetylation of HP1γ at lysine 5 by histone deacetylase 1 (HDAC1) alleviates HP1γ ubiquitination, and the stabilized HP1γ recruits the mediator of DNA damage checkpoint 1 (MDC1) to induce DNA damage repair. Simultaneously, deacetylation modification and MDC1 recruitment enhance the nuclear condensate of HP1γ, which facilitates the chromatin accessibility of genes governing sensitivity to PIs, such as FOS, JUN and CD40. Thus, targeting HP1γ stability using the HDAC1/2 inhibitor, romidepsin, sensitizes PIs treatment and overcomes drug resistance both in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in the acquired drug resistance of MM and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in MM patients.

scholarly journals Direct Kinase-to-Kinase Signaling Mediated by the FHA Phosphoprotein Recognition Domain of the Dun1 DNA Damage Checkpoint Kinase

2003 ◽  
Vol 23 (4) ◽  
pp. 1441-1452 ◽  
Author(s):  
Vladimir I. Bashkirov ◽  
Elena V. Bashkirova ◽  
Edwin Haghnazari ◽  
Wolf-Dietrich Heyer
Keyword(s):  
Dna Damage ◽  
Target Genes ◽  
Genotoxic Stress ◽  
Dna Damage Checkpoint ◽  
Kinase Signaling ◽  
M Cell ◽  
Fha Domain ◽  
Checkpoint Pathway

ABSTRACT The serine-threonine kinase Dun1 contains a forkhead-associated (FHA) domain and functions in the DNA damage checkpoint pathway of Saccharomyces cerevisiae. It belongs to the Chk2 family of checkpoint kinases, which includes S. cerevisiae Rad53 and Mek1, Schizosaccharomyces pombe Cds1, and human Chk2. Dun1 is required for DNA damage-induced transcription of certain target genes, transient G2/M arrest after DNA damage, and DNA damage-induced phosphorylation of the DNA repair protein Rad55. Here we report that the FHA phosphoprotein recognition domain of Dun1 is required for direct phosphorylation of Dun1 by Rad53 kinase in vitro and in vivo. trans phosphorylation by Rad53 does not require the Dun1 kinase activity and is likely to involve only a transient interaction between the two kinases. The checkpoint functions of Dun1 kinase in DNA damage-induced transcription, G2/M cell cycle arrest, and Rad55 phosphorylation are severely compromised in an FHA domain mutant of Dun1. As a consequence, the Dun1 FHA domain mutant displays enhanced sensitivity to genotoxic stress induced by UV, methyl methanesulfonate, and the replication inhibitor hydroxyurea. We show that the Dun1 FHA domain is critical for direct kinase-to-kinase signaling from Rad53 to Dun1 in the DNA damage checkpoint pathway.

Hsp90 regulates the Fanconi anemia DNA damage response pathway

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 5016-5026 ◽  
Author(s):  
Tsukasa Oda ◽  
Toshiya Hayano ◽  
Hidenobu Miyaso ◽  
Nobuhiro Takahashi ◽  
Takayuki Yamashita
Keyword(s):  
Dna Damage ◽  
Fanconi Anemia ◽  
Heat Shock Protein 90 ◽  
Genotoxic Stress ◽  
Cross Linker ◽  
Cellular Tolerance ◽  
Underlying Mechanisms ◽  
Dna Damage Response Pathway

Abstract Heat shock protein 90 (Hsp90) regulates diverse signaling pathways. Emerging evidence suggests that Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), enhance DNA damage-induced cell death, suggesting that Hsp90 may regulate cellular responses to genotoxic stress. However, the underlying mechanisms are poorly understood. Here, we show that the Fanconi anemia (FA) pathway is involved in the Hsp90-mediated regulation of genotoxic stress response. In the FA pathway, assembly of 8 FA proteins including FANCA into a nuclear multiprotein complex, and the complex-dependent activation of FANCD2 are critical events for cellular tolerance against DNA cross-linkers. Hsp90 associates with FANCA, in vivo and in vitro, in a 17-AAG–sensitive manner. Disruption of the FANCA/Hsp90 association by cellular treatment with 17-AAG induces rapid proteasomal degradation and cytoplasmic relocalization of FANCA, leading to impaired activation of FANCD2. Furthermore, 17-AAG promotes DNA cross-linker–induced cytotoxicity, but this effect is much less pronounced in FA pathway-defective cells. Notably, 17-AAG enhances DNA cross-linker–induced chromosome aberrations. In conclusion, our results identify FANCA as a novel client of Hsp90, suggesting that Hsp90 promotes activation of the FA pathway through regulation of intracellular turnover and trafficking of FANCA, which is critical for cellular tolerance against genotoxic stress.

scholarly journals MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence and angiogenic signaling

2017 ◽  
Author(s):  
Cristina Espinosa-Diez ◽  
RaeAnna Wilson ◽  
Namita Chatterjee ◽  
Clayton Hudson ◽  
Rebecca Ruhl ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Targeted Delivery ◽  
Genotoxic Stress ◽  
Telomerase Activity ◽  
Loss Of Function ◽  
Mrn Complex ◽  
Vegf Signaling

AbstractMicroRNAs contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic signaling that is buffered by two distinct microRNAs. We demonstrate that genotoxic stress-induced miR-494 and miR-99b inhibit the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Functionally, gain and loss of function experiments show that miR-494 and miR-99b affect telomerase activity, activate p21 and Rb pathways and diminish angiogenic sproutingin vitroandin vivo. Genetic and pharmacological disruption of VEGFR-2 signaling and the MRN complex reveal a surprising co-dependency of these pathways in regulating endothelial senescence and proliferation. Vascular-targeted delivery of miR-494 decreases both growth factor-induced and tumor angiogenesis in mouse models. Mechanistically, disruption of the MRN complex induced CD44, a known driver of senescence and regulator of VEGF signaling in addition to suppressing IL-13 a stimulator of VEGF signaling. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF signaling to facilitate the onset of senescence and highlight the potential of targeting DNA repair to disrupt pathological angiogenesis.

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 Phosphorylation of the Mdm2 oncoprotein by the c-Abl tyrosine kinase regulates p53 tumor suppression and the radiosensitivity of mice

2016 ◽  
Vol 113 (52) ◽  
pp. 15024-15029 ◽  
Author(s):  
Michael I. Carr ◽  
Justine E. Roderick ◽  
Hong Zhang ◽  
Bruce A. Woda ◽  
Michelle A. Kelliher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Tumor Suppression ◽  
Bone Marrow Failure ◽  
Genotoxic Stress ◽  
Whole Body ◽  
Atm Kinase ◽  
Radiation Induced

The p53 tumor suppressor acts as a guardian of the genome by preventing the propagation of DNA damage-induced breaks and mutations to subsequent generations of cells. We have previously shown that phosphorylation of the Mdm2 oncoprotein at Ser394 by the ATM kinase is required for robust p53 stabilization and activation in cells treated with ionizing radiation, and that loss of Mdm2 Ser394 phosphorylation leads to spontaneous tumorigenesis and radioresistance in Mdm2S394A mice. Previous in vitro data indicate that the c-Abl kinase phosphorylates Mdm2 at the neighboring residue (Tyr393) in response to DNA damage to regulate p53-dependent apoptosis. In this present study, we have generated an Mdm2 mutant mouse (Mdm2Y393F) to determine whether c-Abl phosphorylation of Mdm2 regulates the p53-mediated DNA damage response or p53 tumor suppression in vivo. The Mdm2Y393F mice develop accelerated spontaneous and oncogene-induced tumors, yet display no defects in p53 stabilization and activity following acute genotoxic stress. Although apoptosis is unaltered in these mice, they recover more rapidly from radiation-induced bone marrow ablation and are more resistant to whole-body radiation-induced lethality. These data reveal an in vivo role for c-Abl phosphorylation of Mdm2 in regulation of p53 tumor suppression and bone marrow failure. However, c-Abl phosphorylation of Mdm2 Tyr393 appears to play a lesser role in governing Mdm2-p53 signaling than ATM phosphorylation of Mdm2 Ser394. Furthermore, the effects of these phosphorylation events on p53 regulation are not additive, as Mdm2Y393F/S394A mice and Mdm2S394A mice display similar phenotypes.

In vitro application of sodium arsenite to mice testicular and epididymal organ cultures induces oxidative, biochemical, hormonal, and genotoxic stress

2019 ◽  
Vol 35 (10) ◽  
pp. 660-669
Author(s):  
Naureen Anwar ◽  
Irfan Zia Qureshi
Keyword(s):  
Dna Damage ◽  
Sodium Arsenite ◽  
Genotoxic Stress ◽  
Toxic Effects ◽  
Thiobarbituric Acid Reactive Substance ◽  
Organ Cultures ◽  
Sperm Dna Damage ◽  
Sperm Dna

Arsenic poisoning is well-known for its innumerable toxic and carcinogenic effects. In vivo data on reproductive toxicity are also known but in vitro data are scant. Presently, we evaluated the in vitro toxic effects of sodium arsenite (NaAsO2) on adult mice testes and epididymal tissues using organ cultures. Testicular and epididymal fragments were incubated at 37°C and 33°C, respectively, with 1, 10, 50, and 100 µM concentrations of NaAsO2. Cultures were allowed to incubate for 2 and 24 h. Levels of oxidative stress markers, the reactive oxygen species (ROS) and thiobarbituric acid reactive substance assay (TBARS), antioxidant enzymes, testosterone concentrations, and the extent of sperm DNA damage, were estimated. Results were analyzed statistically at p < 0.05. Results demonstrated both time- and dose-dependent alterations whereby, following 24-h incubation with NaAsO2, substantial increases were noticeable in ROS and TBARS levels and sperm DNA damage ( p < 0.001), while decreases ( p < 0.001) occurred in catalase, peroxidase, and superoxide dismutase levels at 10, 50, and 100 µM concentrations. Incubations for 2 h revealed similar but relatively less toxic effects. Testosterone concentrations decreased significantly only after 24 h of incubation with 50 (1.95 vs. 2.93 ng g−1; p < 0.01) and 100 µM (1.32 vs. 2.93 ng g−1; p < 0.001) NaAsO2 concentrations. The study concluded that exposure of testicular and epididymal tissue fragments to arsenic under in vitro conditions induces rapid and immediate metabolic and genotoxic damage at higher concentrations.

scholarly journals Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yulia Kargapolova ◽  
Rizwan Rehimi ◽  
Hülya Kayserili ◽  
Joanna Brühl ◽  
Konstantinos Sofiadis ◽  
...  
Keyword(s):  
Dna Damage ◽  
De Novo ◽  
Genotoxic Stress ◽  
Cell Types ◽  
In Vitro Assays ◽  
Autophagic Flux ◽  
Chromatin Remodelers ◽  
Human Pathology

AbstractMembers of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance.

scholarly journals BRCA1 Forms a Functional Complex withγ-H2AX as a Late Response to Genotoxic Stress

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Susan A. Krum ◽  
Esther de la Rosa Dalugdugan ◽  
Gustavo A. Miranda-Carboni ◽  
Timothy F. Lane
Keyword(s):  
Dna Damage ◽  
Genotoxic Stress ◽  
Repair Process ◽  
26S Proteasome ◽  
Late Response ◽  
Histone H2ax ◽  
Ubiquitin Ligase Activity ◽  
Functional Complex

Following genotoxic stress, the histone H2AX becomes phosphorylated at serine 139 by the ATM/ATR family of kinases. The tumor suppressor BRCA1, also phosphorylated by ATM/ATR kinases, is one of several proteins that colocalize with phospho-H2AX (γ-H2AX) at sites of active DNA repair. Both the precise mechanism and the purpose of BRCA1 recruitment to sites of DNA damage are unknown. Here we show that BRCA1 andγ-H2AX form an acid-stable biochemical complex on chromatin after DNA damage. Maximal association of BRCA1 withγ-H2AX correlates with reduced globalγ-H2AX levels on chromatin late in the repair process. Since BRCA1 is known to have E3 ubiquitin ligase activityin vitro, we examined H2AX for evidence of ubiquitination. We found that H2AX is ubiquitinated at lysines 119 and 119in vivoand that blockage of 26S proteasome function stabilizesγ-H2AX levels within cells. When BRCA1 levels were reduced, ubiquitination of H2AX was also reduced, and the cells retained higher levels of phosphorylated H2AX. These results indicate that BRCA1 is recruited into stable complexes withγ-H2AX and that the complex is involved in attenuation of theγ-H2AX repair signal after DNA damage.

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