scholarly journals Spontaneous Development of Dental Dysplasia in Aged Parp-1 Knockout Mice

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1157
Author(s):  
Hisako Fujihara ◽  
Tadashige Nozaki ◽  
Masahiro Tsutsumi ◽  
Mayu Isumi ◽  
Shinji Shimoda ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Immunohistochemical Analysis ◽  
Bone Sialoprotein ◽  
Advanced Age ◽  
Computed Tomography Images ◽  
Damage Response ◽  
Dentin Sialoprotein ◽  
Parp 1

Poly(ADP-ribose) polymerase (Parp)-1 catalyzes polyADP-ribosylation using NAD+ and is involved in the DNA damage response, genome stability, and transcription. In this study, we demonstrated that aged Parp-1−/− mouse incisors showed more frequent dental dysplasia in both ICR/129Sv mixed background and C57BL/6 strain compared to aged Parp-1+/+ incisors, suggesting that Parp-1 deficiency could be involved in development of dental dysplasia at an advanced age. Computed tomography images confirmed that dental dysplasia was observed at significantly higher incidences in Parp-1−/− mice. The relative calcification levels of Parp-1−/− incisors were higher in both enamel and dentin (p < 0.05). Immunohistochemical analysis revealed (1) Parp-1 positivity in ameloblasts and odontoblasts in Parp-1+/+ incisor, (2) weaker dentin sialoprotein positivity in dentin of Parp-1−/− incisor, and (3) bone sialoprotein positivity in dentin of Parp-1−/− incisor, suggesting ectopic osteogenic formation in dentin of Parp-1−/− incisor. These results indicate that Parp-1 deficiency promotes odontogenic failure in incisors at an advanced age. Parp-1 deficiency did not affect dentinogenesis during the development of mice, suggesting that Parp-1 is not essential in dentinogenesis during development but is possibly involved in the regulation of continuous dentinogenesis in the incisors at an advanced age.

scholarly journals Author Correction: ID3 regulates the MDC1-mediated DNA damage response in order to maintain genome stability

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Jung-Hee Lee ◽  
Seon-Joo Park ◽  
Gurusamy Hariharasudhan ◽  
Min-Ji Kim ◽  
Sung Mi Jung ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Damage Response ◽  
Maintain Genome Stability

scholarly journals Identification of S-phase DNA damage-response targets in fission yeast reveals conservation of damage-response networks

2016 ◽  
Vol 113 (26) ◽  
pp. E3676-E3685 ◽  
Author(s):  
Nicholas A. Willis ◽  
Chunshui Zhou ◽  
Andrew E. H. Elia ◽  
Johanne M. Murray ◽  
Antony M. Carr ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Replication ◽  
Fission Yeast ◽  
Dna Damage Response ◽  
Cellular Response ◽  
Genome Stability ◽  
Biological Significance ◽  
S Phase ◽  
Damage Response

The cellular response to DNA damage during S-phase regulates a complicated network of processes, including cell-cycle progression, gene expression, DNA replication kinetics, and DNA repair. In fission yeast, this S-phase DNA damage response (DDR) is coordinated by two protein kinases: Rad3, the ortholog of mammalian ATR, and Cds1, the ortholog of mammalian Chk2. Although several critical downstream targets of Rad3 and Cds1 have been identified, most of their presumed targets are unknown, including the targets responsible for regulating replication kinetics and coordinating replication and repair. To characterize targets of the S-phase DDR, we identified proteins phosphorylated in response to methyl methanesulfonate (MMS)-induced S-phase DNA damage in wild-type, rad3∆, and cds1∆ cells by proteome-wide mass spectrometry. We found a broad range of S-phase–specific DDR targets involved in gene expression, stress response, regulation of mitosis and cytokinesis, and DNA replication and repair. These targets are highly enriched for proteins required for viability in response to MMS, indicating their biological significance. Furthermore, the regulation of these proteins is similar in fission and budding yeast, across 300 My of evolution, demonstrating a deep conservation of S-phase DDR targets and suggesting that these targets may be critical for maintaining genome stability in response to S-phase DNA damage across eukaryotes.

scholarly journals PML Colocalizes with and Stabilizes the DNA Damage Response Protein TopBP1

2003 ◽  
Vol 23 (12) ◽  
pp. 4247-4256 ◽  
Author(s):  
Zhi-Xiang Xu ◽  
Anna Timanova-Atanasova ◽  
Rui-Xun Zhao ◽  
Kun-Sang Chang
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Growth Regulation ◽  
Suppressor Gene ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Multifunctional Protein ◽  
Damage Response

ABSTRACT The PML tumor suppressor gene is consistently disrupted by t(15;17) in patients with acute promyelocytic leukemia. Promyelocytic leukemia protein (PML) is a multifunctional protein that plays essential roles in cell growth regulation, apoptosis, transcriptional regulation, and genome stability. Our study here shows that PML colocalizes and associates in vivo with the DNA damage response protein TopBP1 in response to ionizing radiation (IR). Both PML and TopBP1 colocalized with the IR-induced bromodeoxyuridine single-stranded DNA foci. PML and TopBP1 also colocalized with Rad50, Brca1, ATM, Rad9, and BLM. IR and interferon (IFN) coinduce the expression levels of both TopBP1 and PML. In PML-deficient NB4 cells, TopBP1 was unable to form IR-induced foci. All-trans-retinoic acid induced reorganization of the PML nuclear body (NB) and reappearance of the IR-induced TopBP1 foci. Inhibition of PML expression by siRNA is associated with a significant decreased in TopBP1 expression. Furthermore, PML-deficient cells express a low level of TopBP1, and its expression cannot be induced by IR or IFN. Adenovirus-mediated overexpression of PML in PML−/− mouse embryo fibroblasts substantially increased TopBP1 expression, which colocalized with the PML NBs. These studies demonstrated a mechanism of PML-dependent expression of TopBP1. PML overexpression induced TopBP1 protein but not the mRNA expression. Pulse-chase labeling analysis demonstrated that PML overexpression stabilized the TopBP1 protein, suggesting that PML plays a role in regulating the stability of TopBP1 in response to IR. Together, our findings demonstrate that PML regulates TopBP1 functions by association and stabilization of the protein in response to IR-induced DNA damage.

scholarly journals VRK1 Depletion Facilitates the Synthetic Lethality of Temozolomide and Olaparib in Glioblastoma Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Elena Navarro-Carrasco ◽  
Pedro A. Lazo
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Tumor Cell ◽  
Dna Damage Response ◽  
Synthetic Lethality ◽  
Glioblastoma Cell ◽  
Glioblastoma Cells ◽  
Tumor Cell Death ◽  
Damage Response ◽  
Parp 1

BackgroundGlioblastomas treated with temozolomide frequently develop resistance to pharmacological treatments. Therefore, there is a need to find alternative drug targets to reduce treatment resistance based on tumor dependencies. A possibility is to target simultaneously two proteins from different DNA-damage repair pathways to facilitate tumor cell death. Therefore, we tested whether targeting the human chromatin kinase VRK1 by RNA interference can identify this protein as a novel molecular target to reduce the dependence on temozolomide in combination with olaparib, based on synthetic lethality.Materials and MethodsDepletion of VRK1, an enzyme that regulates chromatin dynamic reorganization and facilitates resistance to DNA damage, was performed in glioblastoma cells treated with temozolomide, an alkylating agent used for GBM treatment; and olaparib, an inhibitor of PARP-1, used as sensitizer. Two genetically different human glioblastoma cell lines, LN-18 and LN-229, were used for these experiments. The effect on the DNA-damage response was followed by determination of sequential steps in this process: H4K16ac, γH2AX, H4K20me2, and 53BP1.ResultsThe combination of temozolomide and olaparib increased DNA damage detected by labeling free DNA ends, and chromatin relaxation detected by H4K16ac. The combination of both drugs, at lower doses, resulted in an increase in the DNA damage response detected by the formation of γH2AX and 53BP1 foci. VRK1 depletion did not prevent the generation of DNA damage in TUNEL assays, but significantly impaired the DNA damage response induced by temozolomide and olaparib, and mediated by γH2AX, H4K20me2, and 53BP1. The combination of these drugs in VRK1 depleted cells resulted in an increase of glioblastoma cell death detected by annexin V and the processing of PARP-1 and caspase-3.ConclusionDepletion of the chromatin kinase VRK1 promotes tumor cell death at lower doses of a combination of temozolomide and olaparib treatments, and can be a novel alternative target for therapies based on synthetic lethality.

scholarly journals PARP-1 and its associated nucleases in DNA damage response

DNA Repair ◽  
2019 ◽  
Vol 81 ◽  
pp. 102651 ◽  
Author(s):  
Yijie Wang ◽  
Weibo Luo ◽  
Yingfei Wang
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Damage Response ◽  
Parp 1

scholarly journals Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins

2014 ◽  
Vol 25 (10) ◽  
pp. 1641-1652 ◽  
Author(s):  
Mattia Poletto ◽  
Lisa Lirussi ◽  
David M. Wilson ◽  
Gianluca Tell
Keyword(s):  
Dna Damage Response ◽  
Base Excision Repair ◽  
Genome Stability ◽  
Excision Repair ◽  
Multifunctional Protein ◽  
Protein Levels ◽  
Exact Function ◽  
Damage Response ◽  
Base Excision ◽  
Representative Protein

Nucleophosmin (NPM1) is a multifunctional protein that controls cell growth and genome stability via a mechanism that involves nucleolar–cytoplasmic shuttling. It is clear that NPM1 also contributes to the DNA damage response, yet its exact function is poorly understood. We recently linked NPM1 expression to the functional activation of the major abasic endonuclease in mammalian base excision repair (BER), apurinic/apyrimidinic endonuclease 1 (APE1). Here we unveil a novel role for NPM1 as a modulator of the whole BER pathway by 1) controlling BER protein levels, 2) regulating total BER capacity, and 3) modulating the nucleolar localization of several BER enzymes. We find that cell treatment with the genotoxin cisplatin leads to concurrent relocalization of NPM1 and BER components from nucleoli to the nucleoplasm, and cellular experiments targeting APE1 suggest a role for the redistribution of nucleolar BER factors in determining cisplatin toxicity. Finally, based on the use of APE1 as a representative protein of the BER pathway, our data suggest a function for BER proteins in the regulation of ribogenesis.

scholarly journals Multifunctional Role of ATM/Tel1 Kinase in Genome Stability: From the DNA Damage Response to Telomere Maintenance

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Enea Gino Di Domenico ◽  
Elena Romano ◽  
Paola Del Porto ◽  
Fiorentina Ascenzioni
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Genome Stability ◽  
Genetic Disorder ◽  
Cell Cycle Control ◽  
Premature Aging ◽  
Telomere Maintenance ◽  
Damage Response

The mammalian protein kinase ataxia telangiectasia mutated (ATM) is a key regulator of the DNA double-strand-break response and belongs to the evolutionary conserved phosphatidylinositol-3-kinase-related protein kinases. ATM deficiency causes ataxia telangiectasia (AT), a genetic disorder that is characterized by premature aging, cerebellar neuropathy, immunodeficiency, and predisposition to cancer. AT cells show defects in the DNA damage-response pathway, cell-cycle control, and telomere maintenance and length regulation. Likewise, inSaccharomyces cerevisiae, haploid strains defective in theTEL1gene, the ATM ortholog, show chromosomal aberrations and short telomeres. In this review, we outline the complex role of ATM/Tel1 in maintaining genomic stability through its control of numerous aspects of cellular survival. In particular, we describe how ATM/Tel1 participates in the signal transduction pathways elicited by DNA damage and in telomere homeostasis and its importance as a barrier to cancer development.

scholarly journals Parp-2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice

Blood ◽  
2013 ◽  
Vol 122 (1) ◽  
pp. 44-54 ◽  
Author(s):  
Jordi Farrés ◽  
Juan Martín-Caballero ◽  
Carlos Martínez ◽  
Juan J. Lozano ◽  
Laura Llacuna ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dna Damage Response ◽  
Irradiation Dose ◽  
Essential Role ◽  
Bone Marrow Failure ◽  
Γ Irradiation ◽  
Genetic Inactivation ◽  
Key Points ◽  
Damage Response ◽  
Parp 1

Key Points Genetic inactivation of Parp-2 in mice, but not of Parp-1, resulted in bone marrow failure in response to sublethal γ-irradiation dose. Parp-2 plays an essential role in the DNA damage response in HSPC maintaining hematopoietic homeostasis under stress conditions.

scholarly journals MRE11 is crucial for malaria transmission and its absence affects expression of interconnected networks of key genes essential for life

2020 ◽  
Author(s):  
David S. Guttery ◽  
Abhinay Ramaprasad ◽  
David J. P. Ferguson ◽  
Mohammad Zeeshan ◽  
Rajan Pandey ◽  
...  
Keyword(s):  
Dna Damage Response ◽  
Plasmodium Berghei ◽  
Genome Stability ◽  
Malaria Parasite ◽  
Mosquito Vector ◽  
Parasite Transmission ◽  
Biological Processes ◽  
Cluster Assembly ◽  
Damage Response ◽  
Key Genes

AbstractThe Meiotic Recombination 11 protein (MRE11) plays a key role in DNA damage response and maintenance of genome stability. However, little is known about its function during development of the malaria parasite Plasmodium. Here, we present a functional, ultrastructural and transcriptomic analysis of Plasmodium MRE11 during its life-cycle in both mammalian and mosquito vector hosts. Genetic disruption of Plasmodium berghei mre11 (PbMRE11) results in significant retardation of oocyst development in the mosquito midgut associated with cytoplasmic and nuclear degeneration, along with concomitant ablation of sporogony and subsequent parasite transmission. Further, absence of PbMRE11 results in significant transcriptional downregulation of genes involved in key interconnected biological processes that are fundamental to all eukaryotic life including ribonucleoprotein biogenesis, spliceosome function and iron-sulphur cluster assembly. Overall, our study provides a comprehensive functional analysis of MRE11’s role in Plasmodium development during the mosquito stages and offers a potential target for therapeutic intervention during malaria parasite transmission.

scholarly journals POGZ modulates the DNA damage response in a HP1-dependent manner

2021 ◽  
Author(s):  
John Heath ◽  
Estelle Simo Cheyou ◽  
Steven Findlay ◽  
Vincent Luo ◽  
Edgar Pinedo Carpio ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Dependent Manner ◽  
Dna Double Strand Breaks ◽  
Humoral Immune ◽  
Damage Response

The heterochromatin protein HP1 plays a central role in the maintenance of genome stability, in particular by promoting homologous recombination (HR)-mediated DNA repair. However, little is still known about how HP1 is controlled during this process. Here, we describe a novel function of the POGO transposable element derived with ZNF domain protein (POGZ) in the regulation of HP1 during the DNA damage response in vitro. POGZ depletion delays the resolution of DNA double-strand breaks (DSBs) and correlates with an increased sensitivity to different DNA damaging agents, including the clinically-relevant Cisplatin and Talazoparib. Mechanistically, POGZ promotes homology-directed DNA repair pathways by retaining the BRCA1/BARD1 complex at DSBs, in a HP1-dependent manner. In vivo CRISPR inactivation of Pogz is embryonic lethal and Pogz haplo-insufficiency (Pogz+/Δ) results in a developmental delay, a deficit in intellectual abilities, a hyperactive behaviour as well as a compromised humoral immune response in mice, recapitulating the main clinical features of the White Sutton syndrome (WHSUS). Importantly, Pogz+/Δ mice are radiosensitive and accumulate DSBs in diverse tissues, including the spleen and the brain. Altogether, our findings identify POGZ as an important player in homology-directed DNA repair both in vitro and in vivo, with clinical implications for the WHSUS.

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