scholarly journals Relationship Between DNA Damage and Energy Metabolism: Evidence from DNA Repair Deficiency Syndromes

10.5772/25053 ◽  
2011 ◽  
Author(s):  
Sarah Vose ◽  
James Mitchell
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Energy Metabolism ◽  
Repair Deficiency ◽  
Dna Repair Deficiency

scholarly journals Mutational signatures are jointly shaped by DNA damage and repair

2019 ◽  
Author(s):  
Nadezda V Volkova ◽  
Bettina Meier ◽  
Víctor González-Huici ◽  
Simone Bertolini ◽  
Santiago Gonzalez ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Dna Lesions ◽  
Single Nucleotide Variants ◽  
Mutational Signatures ◽  
Experimental Conditions ◽  
Repair Deficiency ◽  
Dna Repair Deficiency ◽  
Mutation Spectra

AbstractMutations arise when DNA lesions escape DNA repair. To delineate the contributions of DNA damage and DNA repair deficiency to mutagenesis we sequenced 2,717 genomes of wild-type and 53 DNA repair defective C. elegans strains propagated through several generations or exposed to 11 genotoxins at multiple doses. Combining genotoxin exposure and DNA repair deficiency alters mutation rates or leads to unexpected mutation spectra in nearly 40% of all experimental conditions involving 9/11 of genotoxins tested and 32/53 genotypes. For 8/11 genotoxins, signatures change in response to more than one DNA repair deficiency, indicating that multiple genes and pathways are involved in repairing DNA lesions induced by one genotoxin. For many genotoxins, the majority of observed single nucleotide variants results from error-prone translesion synthesis, rather than primary mutagenicity of altered nucleotides. Nucleotide excision repair mends the vast majority of genotoxic lesions, preventing up to 99% of mutations. Analogous mutagenic DNA damage-repair interactions can also be found in cancers, but, except for rare cases, effects are weak owing to the unknown histories of genotoxic exposures and DNA repair status. Overall, our data underscore that mutation spectra are joint products of DNA damage and DNA repair and imply that mutational signatures computationally derived from cancer genomes are more variable than currently anticipated.

Immune checkpoint inhibitor sensitivity of DNA repair deficient tumors

Immunotherapy ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 1205-1213
Author(s):  
Pauline Rochefort ◽  
Françoise Desseigne ◽  
Valérie Bonadona ◽  
Sophie Dussart ◽  
Clélia Coutzac ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Immune Checkpoint ◽  
Genome Stability ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Excision Repair ◽  
Checkpoint Inhibitors ◽  
Repair Deficiency ◽  
Dna Repair Deficiency

Faithful DNA replication is necessary to maintain genome stability and implicates a complex network with several pathways depending on DNA damage type: homologous repair, nonhomologous end joining, base excision repair, nucleotide excision repair and mismatch repair. Alteration in components of DNA repair machinery led to DNA damage accumulation and potentially carcinogenesis. Preclinical data suggest sensitivity to immune checkpoint inhibitors in tumors with DNA repair deficiency. Here, we review clinical studies that explored the use of immune checkpoint inhibitor in patient harboring tumor with DNA repair deficiency.

scholarly journals NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency

2018 ◽  
Vol 115 (8) ◽  
pp. E1876-E1885 ◽  
Author(s):  
Yujun Hou ◽  
Sofie Lautrup ◽  
Stephanie Cordonnier ◽  
Yue Wang ◽  
Deborah L. Croteau ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Hippocampal Neurons ◽  
Therapeutic Potential ◽  
Neuronal Degeneration ◽  
Amyloid Β ◽  
Synaptic Dysfunction ◽  
Amyloid Β Peptide ◽  
Repair Deficiency ◽  
Dna Repair Deficiency

Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer’s disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polβ+/− mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polβ+/− mice have a reduced cerebral NAD+/NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment. NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polβ+/− mice but had no impact on amyloid β peptide (Aβ) accumulation. NR-treated 3xTgAD/Polβ+/− mice exhibited reduced DNA damage, neuroinflammation, and apoptosis of hippocampal neurons and increased activity of SIRT3 in the brain. NR improved cognitive function in multiple behavioral tests and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polβ+/− mice. In general, the deficits between genotypes and the benefits of NR were greater in 3xTgAD/Polβ+/− mice than in 3xTgAD mice. Our findings suggest a pivotal role for cellular NAD+ depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction, and neuronal degeneration in AD. Interventions that bolster neuronal NAD+ levels therefore have therapeutic potential for AD.

scholarly journals The Potential of Using DNA Damage Repair Deficiency As a Biomarker for Cytarabine Response in AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2812-2812
Author(s):  
Clare Crean ◽  
Kienan I Savage ◽  
Ken I Mills
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cell Line ◽  
Cell Lines ◽  
Microarray Data ◽  
Radiation Treatment ◽  
Dna Damage Repair ◽  
Damage Repair ◽  
Repair Deficiency ◽  
Dna Repair Deficiency

Abstract Acute Myeloid Leukemia (AML) is most commonly seen in people over the age of 65 and has a median age of 63. Globally there is an increasingly elderly population so the rate of incidence of AML is set to increase. The therapy landscape for AML has changed little over the past four decades. Cytarabine, first approved in 1969, is still the standard of care induction therapy for AML. There has been only modest improvements in survival rates during this time and there is currently no method of determining which patients will or will not respond to Cytarabine treatment. An assay, developed in 2014, used microarray data to determine which breast cancer patients had a DNA Damage Repair Deficiency (DDRD) and therefore would be more susceptible to DNA damaging agents. A negative DDRD (DDRD-) score predicts that patients do not to have a DNA Repair Deficiency whilst patients with a positive DDRD (DDRD+) score are predicted to have a DNA Repair Deficiency. This assay has been adapted to different solid cancer types such as ovarian and oesophageal cancer. This project has assessed the potential of using the DDRD assay for AML patients. The assay was applied to publically available microarray data of >600 AML patients (TCGA AML data &GSE6891), who were classed as DDRD- or DDRD+. Excluding patients not treated with Cytarabine, this left 639 patients, 405 DDRD+ and 234 DDRD-. Kaplan Meier analysis showed the DDRD+ patients survived significantly (p=0.00047) worse than the DDRD- cohort. Whole exome sequencing was available for 183 patients (131 DDRD+) and the mutations associated with each group were identified. As the DDRD+ patients had the worst outcome, we focused on group. The list of genes more commonly mutated in the DDRD+ patients (>2 instances and >50% occurring in this group) were subjected to pathway analysis. Deregulated pathways included "leukemogenisis" and "cell proliferation and regulation"; however, the most deregulated pathway was "metabolism of nucleobase containing compounds". As Cytarabine is a nucleobase-containing compound, this is potentially a contributing factor as to why these patients responded poorly to this treatment. The assay was applied to microarray data of a panel of myeloid cell lines, and DDRD-(NB4 & SKM1) and a DDRD+(HL-60) cell line were chosen as experimental models. Clonogenic assays, used to analyse the effect of Cytarabine on these cell lines, showed that the DDRD- cell lines were more sensitive with a lower colony growth rate than the DDRD+cell line. DNA damage induction and repair, following cytarabine treatment or 2gy radiation, were measured using RAD51 foci counts. Whilst foci counts were high in all cell lines 2hrs and 4hrs following radiation, the DDRD+ cell line continued to show high levels after 24hrs whereas the levels in the DDRD- cell lines returned to a basal level. RAD51 response to radiation treatment showed that a repair defect is present in DDRD+ cells as they fail to repair the damage induced by radiation. Following treatment with Cytarabine however, few foci were seen in the DDRD+ cell line 2hrs, 4hrs or 24hrs following treatment whereas the DDRD- cell lines responded in a similar fashion to radiation treatment. That RAD51 foci are not present following Cytarabine treatment indicates that Cytarabine fails to induce damage in these cells. The DDRD assay has shown to be an effective method for determining cellular response to Cytarabine in vivo. The non-response of the DDRD+ cell line to Cytarabine suggests that these cells do not elicit a DNA damage or an apoptotic response. This perhaps contributes to their poorer outcome and suggests that Cytarabine is not an effective treatment plan for patients deemed to be DDRD+. Although alternative induction treatment options are currently unavailable for DDRD+ AML patients, this DDRD assay could be used as a biomarker for Cytarabine response in the future. Disclosures No relevant conflicts of interest to declare.

scholarly journals Selective targeting of PARP-2 inhibits androgen receptor signaling and prostate cancer growth through disruption of FOXA1 function

2019 ◽  
Vol 116 (29) ◽  
pp. 14573-14582 ◽  
Author(s):  
Bin Gui ◽  
Fu Gui ◽  
Tomoaki Takai ◽  
Chao Feng ◽  
Xiao Bai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Androgen Receptor ◽  
Damage Repair ◽  
Repair Deficiency ◽  
Selective Targeting ◽  
Dna Repair Deficiency ◽  
Parp 1

Androgen receptor (AR) is a ligand-activated transcription factor and a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated gene expression provides new opportunities for therapeutic intervention. Poly(ADP-ribose) Polymerase (PARP) is a family of enzymes, which posttranslationally modify a range of proteins and regulate many different cellular processes. PARP-1 and PARP-2 are two well-characterized PARP members, whose catalytic activity is induced by DNA-strand breaks and responsible for multiple DNA damage repair pathways. PARP inhibitors are promising therapeutic agents that show synthetic lethality against many types of cancer (including PCa) with homologous recombination (HR) DNA-repair deficiency. Here, we show that, beyond DNA damage repair function, PARP-2, but not PARP-1, is a critical component in AR transcriptional machinery through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to genome-wide prostate-specific enhancer regions. Analyses of PARP-2 expression at both mRNA and protein levels show significantly higher expression of PARP-2 in primary PCa tumors than in benign prostate tissues, and even more so in castration-resistant prostate cancer (CRPC) tumors. Selective targeting of PARP-2 by genetic or pharmacological means blocks interaction between PARP-2 and FOXA1, which in turn attenuates AR-mediated gene expression and inhibits AR-positive PCa growth. Next-generation antiandrogens act through inhibiting androgen synthesis (abiraterone) or blocking ligand binding (enzalutamide). Selective targeting of PARP-2, however, may provide an alternative therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA-repair deficiency status.

DNA Repair Deficiency and Immunotherapy Response

2018 ◽  
Vol 36 (17) ◽  
pp. 1710-1713 ◽  
Author(s):  
Kent W. Mouw ◽  
Alan D. D’Andrea
Keyword(s):  
Dna Repair ◽  
Repair Deficiency ◽  
Dna Repair Deficiency

scholarly journals Mutational signatures are jointly shaped by DNA damage and repair

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nadezda V. Volkova ◽  
Bettina Meier ◽  
Víctor González-Huici ◽  
Simone Bertolini ◽  
Santiago Gonzalez ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Point Mutations ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
C Elegans ◽  
Dna Repair Deficiency ◽  
Dna Alterations ◽  
Repair Pathways

AbstractCells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation. Here we use C. elegans whole genome sequencing to systematically quantify the contributions of these factors to mutational signatures. We analyse 2,717 genomes from wild-type and 53 DNA repair defective backgrounds, exposed to 11 genotoxins, including UV-B and ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin B1, and cisplatin. Combined genotoxic exposure and DNA repair deficiency alters mutation rates or signatures in 41% of experiments, revealing how different DNA alterations induced by the same genotoxin are mended by separate repair pathways. Error-prone translesion synthesis causes the majority of genotoxin-induced base substitutions, but averts larger deletions. Nucleotide excision repair prevents up to 99% of point mutations, almost uniformly across the mutation spectrum. Our data show that mutational signatures are joint products of DNA damage and repair and suggest that multiple factors underlie signatures observed in cancer genomes.

scholarly journals Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Neha Chopra ◽  
Holly Tovey ◽  
Alex Pearson ◽  
Ros Cutts ◽  
Christy Toms ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibition ◽  
Inhibition Activity ◽  
Repair Deficiency ◽  
Dna Repair Deficiency
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