scholarly journals Checkpoint adaptation in repair-deficient cells drives aneuploidy and resistance to genotoxic agents

2018 ◽  
Author(s):  
Olga Vydzhak ◽  
Katharina Bender ◽  
Julia Klermund ◽  
Anke Busch ◽  
Stefanie Reimann ◽  
...  
Keyword(s):  
Dna Repair ◽  
Therapeutic Intervention ◽  
Acquired Resistance ◽  
Molecular Pathways ◽  
Dna Repair Genes ◽  
Human Cancers ◽  
Dna Damaging Agents ◽  
Checkpoint Adaptation ◽  
Repair Genes ◽  
Resistant Cells

AbstractHuman cancers frequently harbour mutations in DNA repair genes, rendering the use of DNA damaging agents as an effective therapeutic intervention. As therapy-resistant cells often arise, it is important to better understand the molecular pathways that drive resistance in order to facilitate the eventual targeting of such processes. We employ repair-defective diploid yeast as a model to demonstrate that, in response to genotoxic challenges, nearly all cells eventually undergo checkpoint adaptation, resulting in the generation of aneuploid cells with whole chromosome losses that have acquired resistance to the initial genotoxic challenge. We demonstrate that adaptation inhibition, either pharmacologically, or genetically, drastically reduces the occurrence of resistant cells. Additionally, the aneuploid phenotypes of the resistant cells can be specifically targeted to induce cytotoxicity. We provide evidence that TORC1 inhibition with rapamycin, in combination with DNA damaging agents, can prevent both checkpoint adaptation and the continued growth of aneuploid resistant cells.

scholarly journals Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

2020 ◽  
Vol 21 (21) ◽  
pp. 8097
Author(s):  
Daria S. Spasskaya ◽  
Nonna I. Nadolinskaia ◽  
Vera V. Tutyaeva ◽  
Yuriy P. Lysov ◽  
Vadim L. Karpov ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Proteasome Inhibition ◽  
26S Proteasome ◽  
Dependent Manner ◽  
Dna Repair Genes ◽  
Damage Resistance ◽  
Dna Damaging Agents ◽  
Mutant Strains ◽  
Repair Genes

Environmental and intracellular factors often damage DNA, but multiple DNA repair pathways maintain genome integrity. In yeast, the 26S proteasome and its transcriptional regulator and substrate Rpn4 are involved in DNA damage resistance. Paradoxically, while proteasome dysfunction may induce hyper-resistance to DNA-damaging agents, Rpn4 malfunction sensitizes yeasts to these agents. Previously, we proposed that proteasome inhibition causes Rpn4 stabilization followed by the upregulation of Rpn4-dependent DNA repair genes and pathways. Here, we aimed to elucidate the key Rpn4 targets responsible for DNA damage hyper-resistance in proteasome mutants. We impaired the Rpn4-mediated regulation of candidate genes using the CRISPR/Cas9 system and tested the sensitivity of mutant strains to 4-NQO, MMS and zeocin. We found that the separate or simultaneous deregulation of 19S or 20S proteasome subcomplexes induced MAG1, DDI1, RAD23 and RAD52 in an Rpn4-dependent manner. Deregulation of RAD23, DDI1 and RAD52 sensitized yeast to DNA damage. Genetic, epigenetic or dihydrocoumarin-mediated RAD52 repression restored the sensitivity of the proteasome mutants to DNA damage. Our results suggest that the Rpn4-mediated overexpression of DNA repair genes, especially RAD52, defines the DNA damage hyper-resistant phenotype of proteasome mutants. The developed yeast model is useful for characterizing drugs that reverse the DNA damage hyper-resistance phenotypes of cancers.

DNA Repair Genes Are Upregulated in Multiple Myeloma (MM) Patients Relapsing after Tandem Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3392-3392
Author(s):  
Guido Tricot ◽  
Fenghuang Zhan ◽  
Yongsheng Huang ◽  
Bart Barlogie ◽  
John Shaughnessy
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Plasma Cells ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Myeloma Cell ◽  
High Dose ◽  
Dna Repair Genes ◽  
High Dose Melphalan ◽  
Repair Genes

Abstract Background: Repair of DNA interstrand crosslinks (ICLs) is considered the major mechanism by which resistance to high and low dose melphalan emerges (Spanswick et al. Blood2002; 100: 224). Enhanced ICL repair occurs via the Fanconi anemia (FA)/ BRCA pathway in myeloma cell lines (Chen et al. Blood2005; 106: 698). The aim of this study was to evaluate if DNA repair genes were indeed upregulated at relapse when compared to baseline in patients enrolled on our Total Therapy 2 protocol. Methods: We compared 51 paired baseline and relapse bone marrow samples for gene expression profiling of CD138 selected plasma cells using the Affimetrix U133 Plus 2.0 microarray. The microarrays were preprocessed using GCOS 1.1 software and normalized using conventional GCOS 1.1 scaling. Baseline and relapse gene expression was compared using the paired Student t test. Results: More than 30 genes related to DNA repair on the microarray were analyzed. We observed significantly higher expression at relapse of FANCA (p=.003), BRCA 1 (p<.001), CHEK1 (p=.006) and FANCG (p=0.03) (Figure 1). In contrast, FANCD2 was down-regulated at relapse (p=.006), while no significant changes in expression of FANCF or DNA mismatch repair genes were seen. Conclusion: Our data supports the concept that DNA repair genes in the FA/BRCA pathway contribute to acquired resistance to melphalan in patients after high dose melphalan transplants and that inhibition of DNA repair by bortezomib, gemcitabine or the CHEK1 kinase inhibitor UCN-01, may reverse such resistance if added to high dose melphalan. DNA Repair Genes in Paired Relapse Samples (N=51) DNA Repair Genes in Paired Relapse Samples (N=51)

Truncating variants in DNA-repair genes and their effect on AAO of hereditary breast cancer

2018 ◽  
Author(s):  
I Sepahi ◽  
U Faust ◽  
M Sturm ◽  
K Bosse ◽  
M Kehrer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Hereditary Breast Cancer ◽  
Dna Repair Genes ◽  
Repair Genes

scholarly journals Coexistence of SOS-Dependent and SOS-Independent Regulation of DNA Repair Genes in Radiation-Resistant Deinococcus Bacteria

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 924
Author(s):  
Laurence Blanchard ◽  
Arjan de Groot
Keyword(s):  
Dna Repair ◽  
Deinococcus Radiodurans ◽  
Dna Repair Genes ◽  
Lesion Bypass ◽  
Radiation Resistant ◽  
Radiation Induced ◽  
Induced Mutagenesis ◽  
High Doses ◽  
Translesion Polymerases ◽  
Repair Genes

Deinococcus bacteria are extremely resistant to radiation and able to repair a shattered genome in an essentially error-free manner after exposure to high doses of radiation or prolonged desiccation. An efficient, SOS-independent response mechanism to induce various DNA repair genes such as recA is essential for radiation resistance. This pathway, called radiation/desiccation response, is controlled by metallopeptidase IrrE and repressor DdrO that are highly conserved in Deinococcus. Among various Deinococcus species, Deinococcus radiodurans has been studied most extensively. Its genome encodes classical DNA repair proteins for error-free repair but no error-prone translesion DNA polymerases, which may suggest that absence of mutagenic lesion bypass is crucial for error-free repair of massive DNA damage. However, many other radiation-resistant Deinococcus species do possess translesion polymerases, and radiation-induced mutagenesis has been demonstrated. At least dozens of Deinococcus species contain a mutagenesis cassette, and some even two cassettes, encoding error-prone translesion polymerase DnaE2 and two other proteins, ImuY and ImuB-C, that are probable accessory factors required for DnaE2 activity. Expression of this mutagenesis cassette is under control of the SOS regulators RecA and LexA. In this paper, we review both the RecA/LexA-controlled mutagenesis and the IrrE/DdrO-controlled radiation/desiccation response in Deinococcus.

Patients with Systemic Sclerosis Present Increased DNA Damage Differentially Associated with DNA Repair Gene Polymorphisms

2014 ◽  
Vol 41 (3) ◽  
pp. 458-465 ◽  
Author(s):  
Gustavo Martelli Palomino ◽  
Carmen L. Bassi ◽  
Isabela J. Wastowski ◽  
Danilo J. Xavier ◽  
Yara M. Lucisano-Valim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Systemic Sclerosis ◽  
Blood Cells ◽  
Gene Polymorphisms ◽  
Peripheral Blood Cells ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Repair Genes

Objective.Patients with systemic sclerosis (SSc) exhibit increased toxicity when exposed to genotoxic agents. In our study, we evaluated DNA damage and polymorphic sites in 2 DNA repair genes (XRCC1Arg399Gln andXRCC4Ile401Thr) in patients with SSc.Methods.A total of 177 patients were studied for DNA repair gene polymorphisms. Fifty-six of them were also evaluated for DNA damage in peripheral blood cells using the comet assay.Results.Compared to controls, the patients as a whole or stratified into major clinical variants (limited or diffuse skin involvement), irrespective of the underlying treatment schedule, exhibited increased DNA damage.XRCC1(rs: 25487) andXRCC4(rs: 28360135) allele and genotype frequencies observed in patients with SSc were not significantly different from those observed in controls; however, theXRCC1Arg399Gln allele was associated with increased DNA damage only in healthy controls and theXRCC4Ile401Thr allele was associated with increased DNA damage in both patients and controls. Further, theXRCC1Arg399Gln allele was associated with the presence of antinuclear antibody and anticentromere antibody. No association was observed between these DNA repair gene polymorphic sites and clinical features of patients with SSc.Conclusion.These results corroborate the presence of genomic instability in SSc peripheral blood cells, as evaluated by increased DNA damage, and show that polymorphic sites of theXRCC1andXRCC4DNA repair genes may differentially influence DNA damage and the development of autoantibodies.

scholarly journals Emergence of a daptomycin-non-susceptible Enterococcus faecium strain that encodes mutations in DNA repair genes after high-dose daptomycin therapy

2016 ◽  
Vol 9 (1) ◽  
Author(s):  
Takashi Matono ◽  
Kayoko Hayakawa ◽  
Risen Hirai ◽  
Akira Tanimura ◽  
Kei Yamamoto ◽  
...  
Keyword(s):  
Dna Repair ◽  
Enterococcus Faecium ◽  
High Dose ◽  
Dna Repair Genes ◽  
Repair Genes ◽  
Faecium Strain

scholarly journals Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer

2015 ◽  
Vol 3 (5) ◽  
pp. 459-466 ◽  
Author(s):  
Yosuke Hirotsu ◽  
Hiroshi Nakagomi ◽  
Ikuko Sakamoto ◽  
Kenji Amemiya ◽  
Toshio Oyama ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Germline Mutations ◽  
Dna Repair Genes ◽  
Panel Analysis ◽  
Breast And Ovarian Cancer ◽  
Repair Genes ◽  
Multigene Panel
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