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

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

scholarly journals DNA repair of clustered lesions in mammalian cells: involvement of non-homologous end-joining

2008 ◽  
Vol 36 (15) ◽  
pp. 4872-4882 ◽  
Author(s):  
S. Malyarchuk ◽  
R. Castore ◽  
L. Harrison
Keyword(s):  
Dna Repair ◽  
Mammalian Cells ◽  
End Joining ◽  
Non Homologous End Joining

The Leukemic Fusion Gene NUP98-HOXD13 Suppresses Non-Homologous End Joining Factors and Impairs DNA Double Strand Break Repair

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 521-521
Author(s):  
David L. Caudell ◽  
Abdul Gafoor A. Puthiyaveetil
Keyword(s):  
Dna Repair ◽  
B Lymphocytes ◽  
Fusion Gene ◽  
Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Class Switch ◽  
Induction Pattern ◽  
Dna Break ◽  
Non Homologous End Joining

Abstract Abstract 521 Chromosomal translocations are hallmark features of hematologic malignancies that often require collaborating mutations for malignant transformation. These secondary mutations can occur spontaneously, or rather, be induced by the primary translocation. Mutations can occur as a result of DNA damage and misrepair with DNA double strand breaks being one of the most serious types of cell damage. Double strand breaks are classically repaired by the non-homologous end joining (NHEJ) mechanism and impaired NHEJ has been shown to promote mutagenesis. Transgenic mice expressing the myeloid leukemic fusion gene NUP98-HOXD13 (NHD13) develop Myelodysplastic syndrome and progress to acute leukemia after acquiring secondary mutations. Our studies have shown that B lymphocyte development and class switch recombination are impaired in stimulated B lymphocytes from NHD13 mice. Based on this, we used in vitro class switch recombination (CSR) to delineate the DNA break induction and repair mechanisms in NHD13 B lymphocytes. Naïve B lymphocytes were harvested from wild type (WT) and NHD13 spleens and cultured in the presence of E.coli Lipopolysaccharide (LPS) and IL-4 to induce CSR. The DNA break induction pattern was determined using phosphorylated H2AX labeling combined with confocal microscopy and flow cytometry. Our results showed that NHD13 B lymphocytes had a comparable break induction pattern, but significantly reduced DNA repair. Analysis of the cell cycle pattern of stimulated B cells at 24 hour intervals showed cell cycle arrest at the G2/M phase at 72 hours following stimulation—a hallmark feature of impaired DNA break repair. We analyzed the expression of classical NHEJ and alternative end joining factors including Ku70, Ku80, DNA Protein Kinase catalytic subunit (DNAPKcs), Xrcc4, DNA ligase 4, Ligase 1, and Ligase 3. Our results showed reduced expression of DNAPKcs, Ligase 4 and Xrcc4 in NHD13 B lymphocytes at 72 hours following stimulation, suggesting that cells failed to initiate NHEJ-mediated DNA repair. Our results suggest that a myeloid leukemic gene can impair the DNA repair mechanism and may indirectly promote mutations necessary for malignant transformation. Disclosures: No relevant conflicts of interest to declare.

p53 Ser15 phosphorylation disrupts the p53–RPA70 complex and induces RPA70-mediated DNA repair in hypoxia

2012 ◽  
Vol 443 (3) ◽  
pp. 811-820 ◽  
Author(s):  
Esha Madan ◽  
Rajan Gogna ◽  
Uttam Pati
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Excision Repair ◽  
Protein A ◽  
Cancer Therapeutics ◽  
End Joining ◽  
Nhej Repair ◽  
Dependent Protein ◽  
Non Homologous End Joining ◽  
Cellular Dna

Cellular stressors are known to inhibit the p53–RPA70 (replication protein A, 70 kDa subunit) complex, and RPA70 increases cellular DNA repair in cancer cells. We hypothesized that regulation of RPA70-mediated DNA repair might be responsible for the inhibition of apoptosis in hypoxic tumours. We have shown that, in cancer cells, hypoxia disrupts the p53–RPA70 complex, thereby enhancing RPA70-mediated NER (nucleotide excision repair)/NHEJ (non-homologous end-joining) repair. In normal cells, RPA70 binds to the p53-NTD (N-terminal domain), whereas this binding is disrupted in hypoxia. Phosphorylation of p53-NTD is a crucial event in dissociating both NTD–RPA70 and p53–RPA70 complexes. Serial mutations at serine and threonine residues in the NTD confirm that p53Ser15 phosphorylation induces dissociation of the p53–RPA70 complex in hypoxia. DNA-PK (DNA-dependent protein kinase) is shown to induce p53Ser15 phosphorylation, thus enhancing RPA70-mediated NER/NHEJ repair. Furthermore, RPA70 gene silencing induces significant increases in cellular apoptosis in the resistant hypoxic cancer cells. We have thus elucidated a novel pathway showing how DNA-PK-mediated p53Ser15 phosphorylation dissociates the p53–RPA70 complex, thus enhancing NER/NHEJ repair, which causes resistance to apoptosis in hypoxic cancer cells. This novel finding may open new strategies in developing cancer therapeutics on the basis of the regulation of RPA70-mediated NER/NHEJ repair.

Sign in / Sign up

Export Citation Format

Share Document