scholarly journals Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors

2018 ◽  
Author(s):  
Manasi Ratnaparkhe ◽  
John Wong ◽  
Pei-Chi Wei ◽  
Mario Hlevnjak ◽  
Thorsten Kolb ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genomic Rearrangements ◽  
End Joining ◽  
Catastrophic Events ◽  
Mouse Tumors ◽  
Damage Repair ◽  
Target Dna ◽  
Recombination Repair ◽  
Non Homologous End Joining

AbstractChromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent chromothripsis or chromoanasynthesis (n= 16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or non-homologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n=68) and glioblastomas (n=32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements.

scholarly journals Proton Irradiation Increases the Necessity for Homologous Recombination Repair Along with the Indispensability of Non-Homologous End Joining

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 889 ◽  
Author(s):  
Klaudia Szymonowicz ◽  
Adam Krysztofiak ◽  
Jansje van der Linden ◽  
Ajvar Kern ◽  
Simon Deycmar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Proton Irradiation ◽  
Negative Impact ◽  
Particle Therapy ◽  
Homologous Recombination Repair ◽  
End Joining ◽  
X Ray ◽  
Recombination Repair ◽  
Non Homologous End Joining

Technical improvements in clinical radiotherapy for maximizing cytotoxicity to the tumor while limiting negative impact on co-irradiated healthy tissues include the increasing use of particle therapy (e.g., proton therapy) worldwide. Yet potential differences in the biology of DNA damage induction and repair between irradiation with X-ray photons and protons remain elusive. We compared the differences in DNA double strand break (DSB) repair and survival of cells compromised in non-homologous end joining (NHEJ), homologous recombination repair (HRR) or both, after irradiation with an equal dose of X-ray photons, entrance plateau (EP) protons, and mid spread-out Bragg peak (SOBP) protons. We used super-resolution microscopy to investigate potential differences in spatial distribution of DNA damage foci upon irradiation. While DNA damage foci were equally distributed throughout the nucleus after X-ray photon irradiation, we observed more clustered DNA damage foci upon proton irradiation. Furthermore, deficiency in essential NHEJ proteins delayed DNA repair kinetics and sensitized cells to both, X-ray photon and proton irradiation, whereas deficiency in HRR proteins sensitized cells only to proton irradiation. We assume that NHEJ is indispensable for processing DNA DSB independent of the irradiation source, whereas the importance of HRR rises with increasing energy of applied irradiation.

scholarly journals Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21- Mediated Early Senescence Signalling

2015 ◽  
Vol 11 (5) ◽  
pp. e1004246 ◽  
Author(s):  
David W. P. Dolan ◽  
Anze Zupanic ◽  
Glyn Nelson ◽  
Philip Hall ◽  
Satomi Miwa ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stochastic Model ◽  
Dna Damage Repair ◽  
End Joining ◽  
Damage Repair ◽  
Non Homologous End Joining

scholarly journals KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

2018 ◽  
Vol 49 (6) ◽  
pp. 2111-2123 ◽  
Author(s):  
Wenlei Yu ◽  
Liang Li ◽  
Guangming Wang ◽  
Wenjun Zhang ◽  
Jun Xu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Jurkat Cells ◽  
Cell Leukemia ◽  
End Joining ◽  
Adult T Cell Leukemia ◽  
Damage Repair ◽  
Repair Efficiency ◽  
Promising Target ◽  
Non Homologous End Joining

Background/Aims: Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease which is highly resistant to chemotherapy. Studies show that enhanced ability of DNA damage repair (DDR) in cancer cells plays a key role in chemotherapy resistance. Here, we suggest that defect in DDR related genes might be a promising target to destroy the genome stability of tumor cells. Methods: Since KU70 is highly expressed in Jurkat cells, one of the most representative cell lines of ATL, we knocked down KU70 by shRNA and analyzed the impact of KU70 deficiency in Jurkat cells as well as in NOD-SCID animal models by western blot, immunofluorescence, flow cytometry and measuring DNA repair efficiency. Results: It is observed that silencing of KU70 resulted in accumulated DNA damage and impaired DDR in Jurkat cells, resulting in more apoptosis, decreased cell proliferation and cell cycle arrest. DNA damage leads to DNA double-strand breaks (DSBs), which are processed by either non-homologous end joining(NHEJ) or homologous recombination(HR). In our study, both NHEJ and HR are impaired because of KU70 defect, accompanied with increased protein level of SHP-1, a dephosphorylation enzyme. In turn, SHP-1 led to dephosphorylation of SIRT1, which further impaired HR repair efficiency. Moreover, KU70 deficiency prolonged survival of Jurkat-xenografted mice. Conclusion: These findings suggest that targeting KU70 is a promising target for ATL and might overcome the existing difficulties in chemotherapy.

scholarly journals Recent Perspectives in Radiation-Mediated DNA Damage and Repair: Role of NHEJ and Alternative Pathways

2021 ◽  
Author(s):  
Ajay Kumar Sharma ◽  
Priyanka Shaw ◽  
Aman Kalonia ◽  
M.H. Yashavarddhan ◽  
Pankaj Chaudhary ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Double Strand Breaks ◽  
Single Strand ◽  
End Joining ◽  
Strand Breaks ◽  
Single Strand Annealing ◽  
Repair Pathways ◽  
Non Homologous End Joining ◽  
Alternative Nhej

Radiation is one of the causative agents for the induction of DNA damage in biological systems. There is various possibility of radiation exposure that might be natural, man-made, intentional, or non-intentional. Published literature indicates that radiation mediated cell death is primarily due to DNA damage that could be a single-strand break, double-strand breaks, base modification, DNA protein cross-links. The double-strand breaks are lethal damage due to the breakage of both strands of DNA. Mammalian cells are equipped with strong DNA repair pathways that cover all types of DNA damage. One of the predominant pathways that operate DNA repair is a non-homologous end-joining pathway (NHEJ) that has various integrated molecules that sense, detect, mediate, and repair the double-strand breaks. Even after a well-coordinated mechanism, there is a strong possibility of mutation due to the flexible nature in joining the DNA strands. There are alternatives to NHEJ pathways that can repair DNA damage. These pathways are alternative NHEJ pathways and single-strand annealing pathways that also displayed a role in DNA repair. These pathways are not studied extensively, and many reports are showing the relevance of these pathways in human diseases. The chapter will very briefly cover the radiation, DNA repair, and Alternative repair pathways in the mammalian system. The chapter will help the readers to understand the basic and applied knowledge of radiation mediated DNA damage and its repair in the context of extensively studied NHEJ pathways and unexplored alternative NHEJ pathways.

scholarly journals Nefarious, but in a Different Way: Comparing the Ecotoxicity, Gene Toxicity and Mutagenicity of Lead (Pb) and Cadmium (Cd) in the Context of Small Mammal Ecotoxicology

2020 ◽  
Author(s):  
Peter Vladislavov Ostoich ◽  
Michaela Beltcheva ◽  
Roumiana Metcheva
Keyword(s):  
Dna Repair ◽  
State Of The Art ◽  
Integrative Approach ◽  
End Joining ◽  
Lead And Cadmium ◽  
Damage Repair ◽  
Organ Specific ◽  
Eukaryotic Dna ◽  
Carcinogenic Metals ◽  
Non Homologous End Joining

Lead and cadmium are long established toxic and carcinogenic metals. Still, the mechanisms of their interaction with eukaryotic DNA are not unequivocally understood. New data provide evidence on the influence of both metals on DNA repair, particularly non-homologous end joining (NHEJ) and mismatch repair (MMR). This may help explain the weak direct mutagenicity of both Pb2+ and Cd2+ ions in the Ames test, as opposed to the proven carcinogenicity of both metals; it has long been proposed that lead and cadmium may induce an imbalance in mammalian systems of DNA damage repair and promote genomic instability. While new evidence for mechanistic interactions of metals with DNA repair emerges, some of the old questions involving dose distribution, pathways of exposure and bioaccumulation/detoxification kinetics still remain valid. To help place the current state of the art in the genetic toxicology of lead and cadmium within the context of ecotoxicology, the current authors propose an integrative approach and offer a review of other authors’ work as well as some of their own data on systemic and organ-specific toxicities in laboratory mice. The current chapter is a comparative analysis of the state of the art in the specific toxicity and genotoxicity of Pb and Cd, presenting some new and little-known information.

scholarly journals The Intermediate Filament Synemin Regulates Non-Homologous End Joining in an ATM-Dependent Manner

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1717 ◽  
Author(s):  
Sara Sofia Deville ◽  
Anne Vehlow ◽  
Sarah Förster ◽  
Ellen Dickreuter ◽  
Kerstin Borgmann ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Intermediate Filament ◽  
Intermediate Filament Protein ◽  
Dependent Manner ◽  
End Joining ◽  
Damage Response ◽  
Non Homologous End Joining ◽  
Filament Protein

The treatment resistance of cancer cells is a multifaceted process in which DNA repair emerged as a potential therapeutic target. DNA repair is predominantly conducted by nuclear events; yet, how extra-nuclear cues impact the DNA damage response is largely unknown. Here, using a high-throughput RNAi-based screen in three-dimensionally-grown cell cultures of head and neck squamous cell carcinoma (HNSCC), we identified novel focal adhesion proteins controlling DNA repair, including the intermediate filament protein, synemin. We demonstrate that synemin critically regulates the DNA damage response by non-homologous end joining repair. Mechanistically, synemin forms a protein complex with DNA-PKcs through its C-terminal tail domain for determining DNA repair processes upstream of this enzyme in an ATM-dependent manner. Our study discovers a critical function of the intermediate filament protein, synemin in the DNA damage response, fundamentally supporting the concept of cytoarchitectural elements as co-regulators of nuclear events.

scholarly journals Mutant huntingtin impairs Ku70-mediated DNA repair

2010 ◽  
Vol 189 (3) ◽  
pp. 425-443 ◽  
Author(s):  
Yasushi Enokido ◽  
Takuya Tamura ◽  
Hikaru Ito ◽  
Anup Arumughan ◽  
Akihiko Komuro ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Abnormal Behavior ◽  
Mutant Huntingtin ◽  
End Joining ◽  
Strand Breaks ◽  
Damage Repair ◽  
Dependent Protein

DNA repair defends against naturally occurring or disease-associated DNA damage during the long lifespan of neurons and is implicated in polyglutamine disease pathology. In this study, we report that mutant huntingtin (Htt) expression in neurons causes double-strand breaks (DSBs) of genomic DNA, and Htt further promotes DSBs by impairing DNA repair. We identify Ku70, a component of the DNA damage repair complex, as a mediator of the DNA repair dysfunction in mutant Htt–expressing neurons. Mutant Htt interacts with Ku70, impairs DNA-dependent protein kinase function in nonhomologous end joining, and consequently increases DSB accumulation. Expression of exogenous Ku70 rescues abnormal behavior and pathological phenotypes in the R6/2 mouse model of Huntington’s disease (HD). These results collectively suggest that Ku70 is a critical regulator of DNA damage in HD pathology.

scholarly journals USP39 promotes non-homologous end-joining repair by poly(ADP-ribose)-induced liquid demixing

2021 ◽  
Author(s):  
Jae Jin Kim ◽  
Seo Yun Lee ◽  
Yiseul Hwang ◽  
Soyeon Kim ◽  
Jee Min Chung ◽  
...  
Keyword(s):  
Dna Repair ◽  
Conclusive Evidence ◽  
Dna Lesions ◽  
Dependent Manner ◽  
Deubiquitinating Enzymes ◽  
End Joining ◽  
Independent Manner ◽  
Recombination Repair ◽  
Non Homologous End Joining

Abstract Mutual crosstalk among poly(ADP-ribose) (PAR), activated PAR polymerase 1 (PARP1) metabolites, and DNA repair machinery has emerged as a key regulatory mechanism of the DNA damage response (DDR). However, there is no conclusive evidence of how PAR precisely controls DDR. Herein, six deubiquitinating enzymes (DUBs) associated with PAR-coupled DDR were identified, and the role of USP39, an inactive DUB involved in spliceosome assembly, was characterized. USP39 rapidly localizes to DNA lesions in a PAR-dependent manner, where it regulates non-homologous end-joining (NHEJ) via a tripartite RG motif located in the N-terminus comprising 46 amino acids (N46). Furthermore, USP39 acts as a molecular trigger for liquid demixing in a PAR-coupled N46-dependent manner, thereby directly interacting with the XRCC4/LIG4 complex during NHEJ. In parallel, the USP39-associated spliceosome complex controls homologous recombination repair in a PAR-independent manner. These findings provide mechanistic insights into how PAR chains precisely control DNA repair processes in the DDR.

scholarly journals Transition from a meiotic to a somatic-like DNA damage response during the pachytene stage in mouse meiosis

2018 ◽  
Author(s):  
Andrea Enguita-Marruedo ◽  
Marta Martín-Ruiz ◽  
Eva García ◽  
Ana Gil-Fernández ◽  
M. Teresa Parra ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Chromosome Translocation ◽  
End Joining ◽  
Principal Mechanism ◽  
Functional Changes ◽  
New Gene ◽  
Non Homologous End Joining ◽  
The Relationship ◽  
Late Stages

AbstractHomologous recombination (HR) is the principal mechanism of DNA repair acting during meiosis and is fundamental for the segregation of chromosomes and the increase of genetic diversity. Nevertheless, non-homologous end joining (NHEJ) mechanisms also act during meiosis, mainly in response to exogenously-induced DNA damage in late stages of first meiotic prophase. In order to better understand the relationship between these two repair pathways, we studied the response to DNA damage during male mouse meiosis after gamma radiation. We clearly discerned two types of responses immediately after treatment. From leptotene to early pachytene, exogenous damage triggered the massive presence of γH2AX throughout the nucleus, which was associated with DNA repair mediated by HR components (DMC1 and RAD51). This early pathway finished with the sequential removal of DMC1 and RAD51 and was no longer inducible at mid pachytene. However, from mid pachytene to diplotene, γH2AX appeared as large discrete foci. This late repair pattern was mediated first by NHEJ, involving Ku70/80 and XRCC4, which were constitutively present, and 53BP1, which appeared at sites of damage soon after irradiation. Nevertheless, 24 hours after irradiation, a HR pathway involving RAD51 but not DMC1 mostly replaced NHEJ. Additionally, we observed the occurrence of synaptonemal complex bridges between bivalents, most likely representing chromosome translocation events that may involve DMC1, RAD51 or 53BP1. Our results reinforce the idea that the early “meiotic” repair pathway that acts by default at the beginning of meiosis is replaced from mid pachytene onwards by a “somatic-like” repair pattern. This shift might be important to resolve DNA damage (either endogenous or exogenous) that could not be repaired by the early meiotic mechanisms, for instance those in the sex chromosomes, which lack a homologous chromosome to repair with. This transition represents another layer of functional changes that occur in meiotic cells during mid pachytene, in addition to epigenetic reprograming, reactivation of transcription, expression of a new gene profile and acquisition of competence to proceed to metaphase.

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