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 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 Knock-In Reporter Mice Demonstrate that DNA Repair by Non-homologous End Joining Declines with Age

PLoS Genetics ◽  
2014 ◽  
Vol 10 (7) ◽  
pp. e1004511 ◽  
Author(s):  
Amita Vaidya ◽  
Zhiyong Mao ◽  
Xiao Tian ◽  
Brianna Spencer ◽  
Andrei Seluanov ◽  
...  
Keyword(s):  
Dna Repair ◽  
End Joining ◽  
Reporter Mice ◽  
Non Homologous End Joining

scholarly journals Genetic Variants of ATM & Non-Homologous End Joining Pathway Genes in Acute Myeloid Leukemia: A South India Case-Control Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5076-5076
Author(s):  
Sugunakar Vuree ◽  
Anuradha Cingeetham ◽  
Dunna Nageswara Rao ◽  
Manjula Gorre ◽  
Sudha Sinha ◽  
...  
Keyword(s):  
Dna Repair ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Case Control Study ◽  
Case Control ◽  
South Indian Population ◽  
End Joining ◽  
Non Homologous End Joining ◽  
Control Study ◽  
Acute Myeloid

Purpose of the study: Deregulated DNA repair is one of the hallmarks of cancers including Acute Myeloid Leukemia (AML), as it results in genomic instability. ATM gene functions as a sensor, activates cascade of events leading to stimulation of multiple DNA damage- responsive signaling pathways. Principal DNA repair mechanism activated in the hematopoietic stem cells is the Non Homologous End Joining (NHEJ) pathway. However, this pathway was shown to be error prone. Functional SNPs in the genes involved in DNA repair might influence the gene expression leading to altered DNA repair which might confer the risk to AML. Materials & Methods: This hospital-based case-control study included 225 AML patients and 326 cancer-free controls from South Indian population. Six polymorphisms of XRCC5, XRCC6, XRCC7 and ATM were genotyped using polymerase chain reaction (PCR)-Restriction Fragment Length Polymorphism (PCR- RFLP) method. Statistical analyses were performed by using SPSS (version20v) and SNPSTAT online tool. Protein-Protein Interaction (PPI) analysis was also done to see the relationship between these genes. Results: We found that there was an elevated risk of AML associated with the XRCC5 VNTR 0R repeat and A allele of 2408G>A polymorphism (p-0.04 and p<0.0001 respectively), the frequencies of G allele (p-<0.0001) of XRCC6 -1310C>G and T allele (p-0.003) of ATM -5144A>T polymorphisms were also significantly increased in AML cases. Further, analyses of the variant genotypes with epidemiological and clinical variables revealed a significant association of the risk genotypes with development and progression of AML. Conclusion: The XRCC5 0R repeat, 2408G>A, XRCC6 -1310 C>G and ATM- 5144A>T polymorphisms, but not XRCC6 -61C>G and XRCC7 6721G>T polymorphisms, play an important role in the pathogenesis of AML. Figure Disclosures No relevant conflicts of interest to declare.

Abstract 2827: Alternative non-homologous end joining DNA repair as therapeutic target in multiple myeloma

2018 ◽  
Author(s):  
Daniele Caracciolo ◽  
Martina Montesano ◽  
Emanuela Altomare ◽  
Grazia Consolo ◽  
Nicola Amodio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Repair ◽  
Therapeutic Target ◽  
End Joining ◽  
Non Homologous End Joining

Anti-silencing factor 1A is associated with genome stability maintenance of mouse preimplantation embryos†

2020 ◽  
Vol 102 (4) ◽  
pp. 817-827
Author(s):  
Kai Deng ◽  
Wanyou Feng ◽  
Xiaohua Liu ◽  
Xiaoping Su ◽  
Erwei Zuo ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Genome Stability ◽  
Mouse Embryos ◽  
Preimplantation Embryos ◽  
End Joining ◽  
Dna Damages ◽  
Developmental Potential ◽  
Damage Repair ◽  
Non Homologous End Joining ◽  
Early Mouse

Abstract Genome stability is critical for the normal development of preimplantation embryos, as DNA damages may result in mutation and even embryo lethality. Anti-silencing factor 1A (ASF1A) is a histone chaperone and enriched in the MII oocytes as a maternal factor, which may be associated with the maintenance of genome stability. Thus, this study was undertaken to explore the role of ASF1A in maintaining the genome stability of early mouse embryos. The ASF1A expressed in the preimplantation embryos and displayed a dynamic pattern throughout the early embryonic development. Inhibition of ASF1A expression decreased embryonic development and increased DNA damages. Overexpression of ASF1A improved the developmental potential and decreased DNA damages. When 293T cells that had been integrated with RGS-NHEJ were co-transfected with plasmids of pcDNA3.1-ASF1A, gRNA-NHEJ, and hCas9, less cells expressed eGFP, indicating that non-homologous end joining was reduced by ASF1A. When 293T cells were co-transfected with plasmids of HR-donor, gRNA-HR, hCas9, and pcDNA3.1-ASF1A, more cells expressed eGFP, indicating that homologous recombination (HR) was enhanced by ASF1A. These results indicate that ASF1A may be associated with the genome stability maintenance of early mouse embryos and this action may be mediated by promoting DNA damage repair through HR pathway.

scholarly journals Short-term calorie restriction enhances DNA repair by non-homologous end joining in mice

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhonghe Ke ◽  
Denis Firsanov ◽  
Brianna Spencer ◽  
Andrei Seluanov ◽  
Vera Gorbunova
Keyword(s):  
Dna Repair ◽  
Calorie Restriction ◽  
End Joining ◽  
Short Term ◽  
Non Homologous End Joining
Sign in / Sign up

Export Citation Format

Share Document