Humans and chimpanzees differ in their cellular response to DNA damage and non-coding sequence elements of DNA repair-associated genes

2008 ◽  
Vol 122 (2) ◽  
pp. 92-102 ◽  
Author(s):  
E. Weis ◽  
D. Galetzka ◽  
H. Herlyn ◽  
E. Schneider ◽  
T. Haaf
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cellular Response ◽  
Coding Sequence ◽  
Sequence Elements

scholarly journals Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Jessica Buck ◽  
Patrick J. C. Dyer ◽  
Hilary Hii ◽  
Brooke Carline ◽  
Mani Kuchibhotla ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Combination Therapy ◽  
Cellular Response ◽  
Molecular Subtype ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Parp Inhibition ◽  
Preclinical Model ◽  
Radiation Induced

Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.

scholarly journals Regulation of cellular response to cisplatin-induced DNA damage and DNA repair in cells overexpressing p185erbB-2 is dependent on the ras signaling pathway

Oncogene ◽  
1997 ◽  
Vol 14 (15) ◽  
pp. 1827-1835 ◽  
Author(s):  
Lily Yen ◽  
Nie Zeng-Rong ◽  
Xiao-Li You ◽  
Stéphane Richard ◽  
Beatrice C Langton-Webster ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Signaling Pathway ◽  
Cellular Response ◽  
Ras Signaling ◽  
Ras Signaling Pathway ◽  
In Cells

scholarly journals Central Role for the Werner Syndrome Protein/Poly(ADP-Ribose) Polymerase 1 Complex in the Poly(ADP-Ribosyl)ation Pathway after DNA Damage

2003 ◽  
Vol 23 (23) ◽  
pp. 8601-8613 ◽  
Author(s):  
Cayetano von Kobbe ◽  
Jeanine A. Harrigan ◽  
Alfred May ◽  
Patricia L. Opresko ◽  
Lale Dawut ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cellular Response ◽  
Werner Syndrome ◽  
Alkylating Agents ◽  
Control Cell ◽  
Dna Damaging Agents ◽  
Werner Syndrome Protein ◽  
Syndrome Protein ◽  
Parp 1

ABSTRACT A defect in the Werner syndrome protein (WRN) leads to the premature aging disease Werner syndrome (WS). Hallmark features of cells derived from WS patients include genomic instability and hypersensitivity to certain DNA-damaging agents. WRN contains a highly conserved region, the RecQ conserved domain, that plays a central role in protein interactions. We searched for proteins that bound to this region, and the most prominent direct interaction was with poly(ADP-ribose) polymerase 1 (PARP-1), a nuclear enzyme that protects the genome by responding to DNA damage and facilitating DNA repair. In pursuit of a functional interaction between WRN and PARP-1, we found that WS cells are deficient in the poly(ADP-ribosyl)ation pathway after they are treated with the DNA-damaging agents H2O2 and methyl methanesulfonate. After cellular stress, PARP-1 itself becomes activated, but the poly(ADP-ribosyl)ation of other cellular proteins is severely impaired in WS cells. Overexpression of the PARP-1 binding domain of WRN strongly inhibits the poly(ADP-ribosyl)ation activity in H2O2-treated control cell lines. These results indicate that the WRN/PARP-1 complex plays a key role in the cellular response to oxidative stress and alkylating agents, suggesting a role for these proteins in the base excision DNA repair pathway.

scholarly journals DNA Damage as a Driver for Growth Delay: Chromosome Instability Syndromes with Intrauterine Growth Retardation

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Benilde García-de Teresa ◽  
Mariana Hernández-Gómez ◽  
Sara Frías
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genomic Instability ◽  
Growth Retardation ◽  
Cellular Response ◽  
Intrauterine Growth Retardation ◽  
Chromosome Instability ◽  
Genetic Material ◽  
Lesion Detection ◽  
Intrauterine Growth

DNA is constantly exposed to endogenous and exogenous mutagenic stimuli that are capable of producing diverse lesions. In order to protect the integrity of the genetic material, a wide array of DNA repair systems that can target each specific lesion has evolved. Despite the availability of several repair pathways, a common general program known as the DNA damage response (DDR) is stimulated to promote lesion detection, signaling, and repair in order to maintain genetic integrity. The genes that participate in these pathways are subject to mutation; a loss in their function would result in impaired DNA repair and genomic instability. When the DDR is constitutionally altered, every cell of the organism, starting from development, will show DNA damage and subsequent genomic instability. The cellular response to this is either uncontrolled proliferation and cell cycle deregulation that ensues overgrowth, or apoptosis and senescence that result in tissue hypoplasia. These diverging growth abnormalities can clinically translate as cancer or growth retardation; both features can be found in chromosome instability syndromes (CIS). The analysis of the clinical, cellular, and molecular phenotypes of CIS with intrauterine growth retardation allows inferring that replication alteration is their unifying feature.

scholarly journals p53-Mediated Regulation of Proliferating Cell Nuclear Antigen Expression in Cells Exposed to Ionizing Radiation

1999 ◽  
Vol 19 (1) ◽  
pp. 12-20 ◽  
Author(s):  
Jin Xu ◽  
Gilbert F. Morris
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Ionizing Radiation ◽  
Proliferating Cell Nuclear Antigen ◽  
Cellular Response ◽  
Nuclear Antigen ◽  
Dominant Negative Mutant ◽  
Mrna Levels ◽  
Mobility Shift ◽  
Proliferating Cell

ABSTRACT The proliferating cell nuclear antigen (PCNA) is a highly conserved cellular protein that functions both in DNA replication and in DNA repair. Exposure of a rat embryo fibroblast cell line (CREF cells) to γ radiation induced simultaneous expression of PCNA with the p53 tumor suppressor protein and the cyclin-dependent kinase inhibitor p21WAF1/Cip1. PCNA mRNA levels transiently increased in serum-starved cells exposed to ionizing radiation, an observation suggesting that the radiation-associated increase in PCNA expression could be dissociated from cell cycle progression. Irradiation of CREF cells activated a transiently expressed PCNA promoter chloramphenicol acetyltransferase construct through p53 binding sequences via a mechanism blocked by a dominant negative mutant p53. Electrophoretic mobility shift assays with nuclear extracts prepared from irradiated CREF cells produced four p53-specific DNA-protein complexes with the PCNA p53 binding site. Addition of monoclonal antibody PAb421 (p53-specific) or AC238 (specific to the transcriptional coactivator p300/CREB binding protein) to the mobility shift assay distinguished different forms of p53 that changed in relative abundance with time after irradiation. These findings suggest a complex cellular response to DNA damage in which p53 transiently activates expression of PCNA for the purpose of limited DNA repair. In a population of nongrowing cells with diminished PCNA levels, this pathway may be crucial to survival following DNA damage.

scholarly journals Lactate Upregulates the Expression of DNA Repair Genes, Causing Intrinsic Resistance of Cancer Cells to Cisplatin

2021 ◽  
Vol 27 ◽  
Author(s):  
Marzia Govoni ◽  
Valentina Rossi ◽  
Giuseppina Di Stefano ◽  
Marcella Manerba
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Cellular Response ◽  
Regulation Of Gene Expression ◽  
Dna Recombination ◽  
Chemotherapeutic Agents ◽  
Glycolytic Metabolism ◽  
Intrinsic Resistance ◽  
The Impact

Intrinsic or acquired drug resistance is one of the major problems compromising the success of antineoplastic treatments. Several evidences correlated some therapeutic failures with changes in cell metabolic asset and in line with these findings, hindering the glycolytic metabolism of cancer cells via lactate dehydrogenase (LDH) inhibition was found to overcome the resistance to chemotherapeutic agents. Lactate, the product of LDH reaction, was shown to be involved in epigenetic regulation of gene expression. The experiments described in this paper were aimed at highlighting a possible direct effect of lactate in modifying the response of cancer cells to a chemotherapeutic treatment. To discriminate between the effects potentially caused by glycolytic metabolism from those directly referable to lactate, we selected cancer cell lines able to grow in glucose deprived conditions and evaluated the impact of lactate on the cellular response to cisplatin-induced DNA damage. In lactate-exposed cells we observed a reduced efficacy of cisplatin, which was associated with reduced signatures of DNA damage, enhanced DNA recombination competence and increased expression of a panel of genes involved in DNA repair. The identified genes take part in mismatch and nucleotide excision repair pathways, which were found to contribute in restoring the cisplatin-induced DNA damage. The obtained results suggest that this metabolite could play a role in reducing the efficacy of antineoplastic treatments.

scholarly journals DNA damage invokes mitophagy through a pathway involving Spata18

2020 ◽  
Vol 48 (12) ◽  
pp. 6611-6623 ◽  
Author(s):  
Xiuli Dan ◽  
Mansi Babbar ◽  
Anthony Moore ◽  
Noah Wechter ◽  
Jingyan Tian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Intracellular Signaling ◽  
Cellular Response ◽  
Control Process ◽  
Atp Production ◽  
Mitochondrial Functions ◽  
Quality Control Process ◽  
Primary Fibroblasts ◽  
Important Player

Abstract Mitochondria are vital for cellular energy supply and intracellular signaling after stress. Here, we aimed to investigate how mitochondria respond to acute DNA damage with respect to mitophagy, which is an important mitochondrial quality control process. Our results show that mitophagy increases after DNA damage in primary fibroblasts, murine neurons and Caenorhabditis elegans neurons. Our results indicate that modulation of mitophagy after DNA damage is independent of the type of DNA damage stimuli used and that the protein Spata18 is an important player in this process. Knockdown of Spata18 suppresses mitophagy, disturbs mitochondrial Ca2+ homeostasis, affects ATP production, and attenuates DNA repair. Importantly, mitophagy after DNA damage is a vital cellular response to maintain mitochondrial functions and DNA repair.

scholarly journals N6-Methyladenosine, DNA Repair, and Genome Stability

2021 ◽  
Vol 8 ◽  
Author(s):  
Fei Qu ◽  
Pawlos S. Tsegay ◽  
Yuan Liu
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cellular Response ◽  
Genome Stability ◽  
Fine Tuning ◽  
Genome Integrity ◽  
Cell Renewal ◽  
The Novel ◽  
Cellular Sensitivity

N6-methyladenosine (m6A) modification in mRNAs and non-coding RNAs is a newly identified epitranscriptomic mark. It provides a fine-tuning of gene expression to serve as a cellular response to endogenous and exogenous stimuli. m6A is involved in regulating genes in multiple cellular pathways and functions, including circadian rhythm, cell renewal, differentiation, neurogenesis, immunity, among others. Disruption of m6A regulation is associated with cancer, obesity, and immune diseases. Recent studies have shown that m6A can be induced by oxidative stress and DNA damage to regulate DNA repair. Also, deficiency of the m6A eraser, fat mass obesity-associated protein (FTO) can increase cellular sensitivity to genotoxicants. These findings shed light on the novel roles of m6A in modulating DNA repair and genome integrity and stability through responding to DNA damage. In this mini-review, we discuss recent progress in the understanding of a unique role of m6As in mRNAs, lncRNAs, and microRNAs in DNA damage response and regulation of DNA repair and genome integrity and instability.

scholarly journals TEL/JAK2 tyrosine kinase inhibits DNA repair in the presence of amifostine.

2002 ◽  
Vol 49 (1) ◽  
pp. 121-128 ◽  
Author(s):  
Ewa Gloc ◽  
Mariusz Warszawski ◽  
Wojciech Młynarski ◽  
Małgorzata Stolarska ◽  
Grazyna Hoser ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Tyrosine Kinase ◽  
Cellular Response ◽  
Catalytic Domain ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Cell Types ◽  
Transformed Cells ◽  
Dna Damage And Repair

The TEL/JAK2 chromosomal translocation (t(9;12)(p24;p13)) is associated with T cell childhood acute lymphoblastic leukemia. The TEL/JAK2 fusion protein contains the JAK2 catalytic domain and the TEL-specific oligomerization domain. TEL-mediated oligomerization of the TEL/JAK2 proteins results in the constitutive activation of the tyrosine kinase activity. Leukemia cells expressing TEL/JAK2 tyrosine kinase become resistant to anti-neoplastic drugs. Amifostine is a pro-drug which can selectively protect normal tissues against the toxicity of anticancer drugs and radiation. We investigated the effects of amifostine on idarubicin-induced DNA damage and repair in murine pro-B lymphoid BaF3 cells and BaF3-TEL/JAK2-transformed cells using alkaline single cell gel electrophoresis (comet assay). Idarubicin induced DNA damage in both cell types but amifostine reduced its extent in control non-transformed BaF3 cells and enhanced it in TEL/JAK2-transformed cells. The transformed cells did not show measurable DNA repair after exposure to amifostine and idarubicin, but cells treated only with idarubicin were able to recover within a 60-min incubation. Because TEL/JAK2-transformed cells can be considered as model cells for certain human leukemias and lymphomas we anticipate an enhancement of idarubicin cytotoxicity by amifostine in these diseases. Moreover, TEL/JAK2 tyrosine kinase might be involved in cellular response to DNA damage. Amifostine could promote apoptosis or lower the threshold for apoptosis induction dependent on TEL/JAK2 activation.

scholarly journals DNA Repair Protein Rad55 Is a Terminal Substrate of the DNA Damage Checkpoints

2000 ◽  
Vol 20 (12) ◽  
pp. 4393-4404 ◽  
Author(s):  
Vladimir I. Bashkirov ◽  
Jeff S. King ◽  
Elena V. Bashkirova ◽  
Jacqueline Schmuckli-Maurer ◽  
Wolf-Dietrich Heyer
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cellular Response ◽  
Time Course ◽  
Gamma Ray ◽  
Genotoxic Stress ◽  
Dna Damage Checkpoint ◽  
Recombinational Repair ◽  
Checkpoint Control ◽  
Repair Protein

ABSTRACT Checkpoints, which are integral to the cellular response to DNA damage, coordinate transient cell cycle arrest and the induced expression of DNA repair genes after genotoxic stress. DNA repair ensures cellular survival and genomic stability, utilizing a multipathway network. Here we report evidence that the two systems, DNA damage checkpoint control and DNA repair, are directly connected by demonstrating that the Rad55 double-strand break repair protein of the recombinational repair pathway is a terminal substrate of DNA damage and replication block checkpoints. Rad55p was specifically phosphorylated in response to DNA damage induced by the alkylating agent methyl methanesulfonate, dependent on an active DNA damage checkpoint. Rad55p modification was also observed after gamma ray and UV radiation. The rapid time course of phosphorylation and the recombination defects identified in checkpoint-deficient cells are consistent with a role of the DNA damage checkpoint in activating recombinational repair. Rad55p phosphorylation possibly affects the balance between different competing DNA repair pathways.

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