scholarly journals Regulation of the cognitive aging process by the transcriptional repressor RP58

2021 ◽  
Author(s):  
Tomoko Tanaka ◽  
Shinobu Hirai ◽  
Hiroyuki Manabe ◽  
Kentaro Endo ◽  
Hiroko Shimbo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Knockout Mice ◽  
Cognitive Aging ◽  
Critical Role ◽  
Harmful Effect ◽  
Transcriptional Repressor ◽  
Repair Pathway ◽  
Wild Type

Aging involves a decline in physiology which is a natural event in all living organisms. An accumulation of DNA damage contributes to the progression of aging. DNA is continually damaged by exogenous sources and endogenous sources. If the DNA repair pathway operates normally, DNA damage is not life threatening. However, impairments of the DNA repair pathway may result in an accumulation of DNA damage, which has a harmful effect on health and causes an onset of pathology. RP58, a zinc-finger transcriptional repressor, plays a critical role in cerebral cortex formation. Recently, it has been reported that the expression level of RP58 decreases in the aged human cortex. Furthermore, the role of RP58 in DNA damage is inferred by the involvement of DNMT3, which acts as a co-repressor for RP58, in DNA damage. Therefore, RP58 may play a crucial role in the DNA damage associated with aging. In the present study, we investigated the role of RP58 in aging. We used RP58 hetero-knockout and wild-type mice in adolescence, adulthood, or old age. We performed immunohistochemistry to determine whether microglia and DNA damage markers responded to the decline in RP58 levels. Furthermore, we performed an object location test to measure cognitive function, which decline with age. We found that the wild-type mice showed an increase in single-stranded DNA and gamma-H2AX foci. These results indicate an increase in DNA damage or dysfunction of DNA repair mechanisms in the hippocampus as age-related changes. Furthermore, we found that, with advancing age, both the wild-type and hetero-knockout mice showed an impairment of spatial memory for the object and increase in reactive microglia in the hippocampus. However, the RP58 hetero-knockout mice showed these symptoms earlier than the wild-type mice did. These results suggest that a decline in RP58 level may lead to the progression of aging.

scholarly journals Disruption of CXCR6 Ameliorates Kidney Inflammation and Fibrosis in Deoxycorticosterone Acetate/Salt Hypertension

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuanbo Wu ◽  
Changlong An ◽  
Xiaogao Jin ◽  
Zhaoyong Hu ◽  
Yanlin Wang
Keyword(s):  
Knockout Mice ◽  
Critical Role ◽  
Kidney Injury ◽  
Wild Type ◽  
Salt Treatment ◽  
Hypertensive Nephropathy ◽  
Deoxycorticosterone Acetate ◽  
Kidney Fibrosis ◽  
Salt Hypertension

AbstractCirculating cells have a pathogenic role in the development of hypertensive nephropathy. However, how these cells infiltrate into the kidney are not fully elucidated. In this study, we investigated the role of CXCR6 in deoxycorticosterone acetate (DOCA)/salt-induced inflammation and fibrosis of the kidney. Following uninephrectomy, wild-type and CXCR6 knockout mice were treated with DOCA/salt for 3 weeks. Blood pressure was similar between wild-type and CXCR6 knockout mice at baseline and after treatment with DOCA/salt. Wild-type mice develop significant kidney injury, proteinuria, and kidney fibrosis after three weeks of DOCA/salt treatment. CXCR6 deficiency ameliorated kidney injury, proteinuria, and kidney fibrosis following treatment with DOCA/salt. Moreover, CXCR6 deficiency inhibited accumulation of bone marrow–derived fibroblasts and myofibroblasts in the kidney following treatment with DOCA/salt. Furthermore, CXCR6 deficiency markedly reduced the number of macrophages and T cells in the kidney after DOCA/salt treatment. In summary, our results identify a critical role of CXCR6 in the development of inflammation and fibrosis of the kidney in salt-sensitive hypertension.

scholarly journals Role of Mammalian Rad54 in Telomere Length Maintenance

2003 ◽  
Vol 23 (16) ◽  
pp. 5572-5580 ◽  
Author(s):  
Isabel Jaco ◽  
Purificación Muñoz ◽  
Fermín Goytisolo ◽  
Joanna Wesoly ◽  
Susan Bailey ◽  
...  
Keyword(s):  
Dna Repair ◽  
Telomere Length ◽  
Essential Role ◽  
Repair Pathway ◽  
Wild Type ◽  
Putative Role ◽  
Telomere Capping ◽  
Chromosome Fusions ◽  
Deficient Mice

ABSTRACT The homologous recombination (HR) DNA repair pathway participates in telomere length maintenance in yeast but its putative role at mammalian telomeres is unknown. Mammalian Rad54 is part of the HR machinery, and Rad54-deficient mice show a reduced HR capability. Here, we show that Rad54-deficient mice also show significantly shorter telomeres than wild-type controls, indicating that Rad54 activity plays an essential role in telomere length maintenance in mammals. Rad54 deficiency also resulted in an increased frequency of end-to-end chromosome fusions involving telomeres compared to the controls, suggesting a putative role of Rad54 in telomere capping. Finally, the study of mice doubly deficient for Rad54 and DNA-PKcs showed that telomere fusions due to DNA-PKcs deficiency were not rescued in the absence of Rad54, suggesting that they are not mediated by Rad54 activity.

Role Of Base Excision Repair Associated AP Nuclease Activity In The Induction Of Homologous Recombination Repair Pathway and Survival Of MM Cells Following DNA Damage

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1248-1248
Author(s):  
Subodh Kumar ◽  
Jagannath Pal ◽  
Jialan Shi ◽  
Puru Nanjappa ◽  
Maria Gkotzamanidou ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Critical Role ◽  
Nuclease Activity ◽  
Repair Pathway ◽  
Control Shrna ◽  
Base Excision

Abstract We have previously shown that endonuclease activity is deregulated in myeloma and suppression of base excision repair (BER) associated apurinic/apyrimidinic endonuclease (APE) activity, mediated chemically or transgenically, reduces homologous recombination (HR) and genomic instability in multiple myeloma (MM). The purpose of this study was to investigate the role of BER-specific AP nucleases APE1 and APE2, separately or together, in the activation of HR pathway following exposure of MM cells to different DNA damaging agents and unravel possible mechanism/s and translational significance of this cross talk between two repair pathways in MM. We transduced MM cells with lentivirus-based shRNAs, either control (CS) or those targeting APE1, APE2, or both (APE1/2; double knockdown) and selected the transduced cells in puromycin. Knockdowns were confirmed by Western blotting and Q-PCR. Using evaluation by Q-PCR we observed that whereas APE2 was suppressed by 80% in APE2- as well as double-knockdown cells, it was upregulated by 70% in APE1 knock down cells. These data indicate that certain level of AP nuclease activity is probably required by MM cell to function and is consistent with a 25-30% reduced proliferation rate of double-knockdown cells under spontaneous condition. To study the impact of these modulations on ability of cells to activate HR-mediated repair pathway in response to DNA damage, the cells were exposed to either UV (20 J/m2) and incubated for 2 and 48 hrs or melphalan (2.5 µM) treatment for 24 hrs, and then incubation for further 1 and 24 hrs and evaluated for RAD51 and γ-H2AX foci. Following UV treatment, RAD51 foci were detected in 91%, 48%, 49%, and 28% of cells transduced with control, APE1, APE2, or both shRNAs, respectively. Similary melphalan treatment induced RAD51 foci in 76% of control shRNA transduced cells whereas only in 46%, 47%, and 27% of APE1, APE2, and APE1/2-knockdown cells. These data show that AP nuclease activity is involved in DNA damaging agent-induced activation of HR repair pathway. Impact of the suppression of AP nucleases was also assessed on cell proliferation at 48 hrs after treatment with melphalan. Viability of cells lacking APE1, APE2, and APE1/2 relative to control shRNA-transduced cells was reduced by 28%, 26%, and 43% (P<0.00005), respectively, within 48 hrs of treatment. In summary, we show that: 1) AP nuclease activity plays a critical role in the activation of HR-mediated DNA repair and survival of MM cells following DNA damage; 2) Although suppression of APE1 or APE2 alone does not significantly affect spontaneous proliferation rates, simultaneous suppression of both reduces proliferation by ∼25-30%; 3) Suppression of APE1 leads to induction of APE2, indicating that certain level of AP nuclease activity (from either APE1 or APE2) is required by MM cell to function and is consistent with the reduced proliferation rate of double-knockdown cells; 4) Simultaneous suppression of both AP nucleases impairs the activation of HR repair following DNA damage. These data combined with our previous observations conclude that AP nucleases (APE1 and APE2) play critical role in HR-mediated repair and survival of MM cells following DNA damage and are important targets to reduce genomic instability as well as to sensitize MM cells to radio/chemotherapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Type 1 Insulin-Like Growth Factor Receptor (IGF-IR) Pathway Is Mandatory for the Follistatin-Induced Skeletal Muscle Hypertrophy

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 241-253 ◽  
Author(s):  
S. Kalista ◽  
O. Schakman ◽  
H. Gilson ◽  
P. Lause ◽  
B. Demeulder ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Knockout Mice ◽  
Muscle Hypertrophy ◽  
Critical Role ◽  
Muscle Growth ◽  
Dominant Negative ◽  
Wild Type ◽  
Myostatin Inhibition

Myostatin inhibition by follistatin (FS) offers a new approach for muscle mass enhancement. The aim of the present study was to characterize the mediators responsible for the FS hypertrophic action on skeletal muscle in male mice. Because IGF-I and IGF-II, two crucial skeletal muscle growth factors, are induced by myostatin inhibition, we assessed their role in FS action. First, we tested whether type 1 IGF receptor (IGF-IR) is required for FS-induced hypertrophy. By using mice expressing a dominant-negative IGF-IR in skeletal muscle, we showed that IGF-IR inhibition blunted by 63% fiber hypertrophy caused by FS. Second, we showed that FS caused the same degree of fiber hypertrophy in wild-type and IGF-II knockout mice. We then tested the role of the signaling molecules stimulated by IGF-IR, in particular the Akt/mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (S6K) pathway. We investigated whether Akt phosphorylation is required for the FS action. By cotransfecting a dominant-negative form of Akt together with FS, we showed that Akt inhibition reduced by 65% fiber hypertrophy caused by FS. Second, we evaluated the role of mTOR in FS action. Fiber hypertrophy induced by FS was reduced by 36% in rapamycin-treated mice. Finally, because the activity of S6K is increased by FS, we tested its role in FS action. FS caused the same degree of fiber hypertrophy in wild-type and S6K1/2 knockout mice. In conclusion, the IGF-IR/Akt/mTOR pathway plays a critical role in FS-induced muscle hypertrophy. In contrast, induction of IGF-II expression and S6K activity by FS are not required for the hypertrophic action of FS.

scholarly journals Suppression of Chlamydial Pathogenicity by Nonspecific CD8+ T Lymphocytes

2020 ◽  
Vol 88 (10) ◽  
Author(s):  
Lingxiang Xie ◽  
Conghui He ◽  
Jianlin Chen ◽  
Lingli Tang ◽  
Zhiguang Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
Knockout Mice ◽  
Critical Role ◽  
Wild Type ◽  
Tubal Infertility ◽  
Content Type ◽  
Chlamydia Muridarum ◽  
Chlamydial Antigen

ABSTRACT Chlamydia trachomatis, a leading infectious cause of tubal infertility, induces upper genital tract pathology, such as hydrosalpinx, which can be modeled with Chlamydia muridarum infection in mice. Following C. muridarum inoculation, wild-type mice develop robust hydrosalpinx, but OT1 mice fail to do so because their T cell receptors are engineered to recognize a single ovalbumin epitope (OVA457-462). These observations have demonstrated a critical role of Chlamydia-specific T cells in chlamydial pathogenicity. In the current study, we have also found that OT1 mice can actively inhibit chlamydial pathogenicity. First, depletion of CD8+ T cells from OT1 mice led to the induction of significant hydrosalpinx by Chlamydia, indicating that CD8+ T cells are necessary to inhibit chlamydial pathogenicity. Second, adoptive transfer of CD8+ T cells from OT1 mice to CD8 knockout mice significantly reduced chlamydial induction of hydrosalpinx, demonstrating that OT1 CD8+ T cells are sufficient for attenuating chlamydial pathogenicity in CD8 knockout mice. Finally, CD8+ T cells from OT1 mice also significantly inhibited hydrosalpinx development in wild-type mice following an intravaginal inoculation with Chlamydia. Since T cells in OT1 mice are engineered to recognize only the OVA457-462 epitope, the above observations have demonstrated a chlamydial antigen-independent immune mechanism for regulating chlamydial pathogenicity. Further characterization of this mechanism may provide information for developing strategies to reduce infertility-causing pathology induced by infections.

scholarly journals A Role for Histone H2B During Repair of UV-Induced DNA Damage in Saccharomyces cerevisiae

Genetics ◽  
2002 ◽  
Vol 160 (4) ◽  
pp. 1375-1387
Author(s):  
Emmanuelle M D Martini ◽  
Scott Keeney ◽  
Mary Ann Osley
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Chromatin Structure ◽  
Specific Effect ◽  
Cell Killing ◽  
Cyclobutane Pyrimidine Dimers ◽  
Histone H2b ◽  
Uv Sensitivity ◽  
Pyrimidine Dimers

Abstract To investigate the role of the nucleosome during repair of DNA damage in yeast, we screened for histone H2B mutants that were sensitive to UV irradiation. We have isolated a new mutant, htb1-3, that shows preferential sensitivity to UV-C. There is no detectable difference in bulk chromatin structure or in the number of UV-induced cis-syn cyclobutane pyrimidine dimers (CPD) between HTB1 and htb1-3 strains. These results suggest a specific effect of this histone H2B mutation in UV-induced DNA repair processes rather than a global effect on chromatin structure. We analyzed the UV sensitivity of double mutants that contained the htb1-3 mutation and mutations in genes from each of the three epistasis groups of RAD genes. The htb1-3 mutation enhanced UV-induced cell killing in rad1Δ and rad52Δ mutants but not in rad6Δ or rad18Δ mutants, which are defective in postreplicational DNA repair (PRR). When combined with other mutations that affect PRR, the histone mutation increased the UV sensitivity of strains with defects in either the error-prone (rev1Δ) or error-free (rad30Δ) branches of PRR, but did not enhance the UV sensitivity of a strain with a rad5Δ mutation. When combined with a ubc13Δ mutation, which is also epistatic with rad5Δ, the htb1-3 mutation enhanced UV-induced cell killing. These results suggest that histone H2B acts in a novel RAD5-dependent branch of PRR.

scholarly journals DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Takayuki Saitoh ◽  
Tsukasa Oda
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Tumor Microenvironment ◽  
Dna Damage Response ◽  
Genetic Instability ◽  
Dna Repair Mechanisms ◽  
Damage Response ◽  
Repair Mechanisms

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.

scholarly journals The critical role of T cells in glucocorticoid-induced osteoporosis

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Song ◽  
Lijuan Cao ◽  
Rui Liu ◽  
Hui Ma ◽  
Yanan Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Steady State ◽  
Side Effects ◽  
Critical Role ◽  
Wild Type ◽  
Receptor Activator ◽  
Steady State Levels ◽  
Induced Apoptosis

AbstractGlucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.

scholarly journals Host DNA Repair Proteins in Response toPseudomonas aeruginosain Lung Epithelial Cells and in Mice

2010 ◽  
Vol 79 (1) ◽  
pp. 75-87 ◽  
Author(s):  
Min Wu ◽  
Huang Huang ◽  
Weidong Zhang ◽  
Shibichakravarthy Kannan ◽  
Andrew Weaver ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Epithelial Cells ◽  
Critical Role ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Myeloperoxidase Activity ◽  
Gram Negative ◽  
Lung Epithelial ◽  
Dna Repair Proteins

ABSTRACTAlthough DNA repair proteins in bacteria are critical for pathogens' genome stability and for subverting the host defense, the role of host DNA repair proteins in response to bacterial infection is poorly defined. Here, we demonstrate, for the first time, that infection with the Gram-negative bacteriumPseudomonas aeruginosasignificantly altered the expression and enzymatic activity of 8-oxoguanine DNA glycosylase (OGG1) in lung epithelial cells. Downregulation of OGG1 by a small interfering RNA strategy resulted in severe DNA damage and cell death. In addition, acetylation of OGG1 is required for host responses to bacterial genotoxicity, as mutations of OGG1 acetylation sites increased Cockayne syndrome group B (CSB) protein expression. These results also indicate that CSB may be involved in DNA repair activity during infection. Furthermore, OGG1 knockout mice exhibited increased lung injury after infection withP. aeruginosa, as demonstrated by higher myeloperoxidase activity and lipid peroxidation. Together, our studies indicate thatP. aeruginosainfection induces significant DNA damage in host cells and that DNA repair proteins play a critical role in the host response toP. aeruginosainfection, serving as promising targets for the treatment of this condition and perhaps more broadly Gram-negative bacterial infections.

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