The Human L1 Element Causes DNA Double-Strand Breaks in Breast Cancer

2006 ◽  
Author(s):  
Prescott L. Deininger
Keyword(s):  
Breast Cancer ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
L1 Element

The nucleoside antagonist cordycepin causes DNA double strand breaks in breast cancer cells

2012 ◽  
Vol 30 (5) ◽  
pp. 1917-1925 ◽  
Author(s):  
Hong Jue Lee ◽  
Petra Burger ◽  
Marianne Vogel ◽  
Klaus Friese ◽  
Ansgar Brüning
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

Topoisomerase-2alpha (T-2a), Ki67, Her-2 and response to neoadjuvant anthracycline-containing chemotherapy in breast cancer. A prospective, correlation study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21094-21094
Author(s):  
M. Bari ◽  
D. Sartori ◽  
P. Zambenedetti ◽  
G. Tacchetti ◽  
U. Sicari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cellular Proliferation ◽  
Locally Advanced Breast Cancer ◽  
Locally Advanced ◽  
Correlation Study ◽  
Double Strand Breaks ◽  
Chromosome 17 ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Her 2

21094 Background: T-2a creates a reversible double-strand DNA break allowing DNA doubling. Anthracyclines (A) stabilize the DNA double-strand breaks, and T-2a is probably the primary molecular target of A. Due to the close location of T-2a and Her-2 genes on chromosome 17, T-2a gene aberrations are mainly associated with Her-2 gene amplification; while a correlation exists between Her-2 amplification and protein overexpression this is not true for T-2a. A linear correlation between T-2a and Ki67 labeling indices was found, suggesting that both essentially reflect cellular proliferation. The correlation between T-2a overexpression and both Her-2 and Ki67 was investigated in a series of consecutive patients undergone neoadjuvant A-containing chemotherapy for locally-advanced breast cancer. Material and Methods: T-2a expression was measured by means of monoclonal antibody Ki-S1; thresholds (ts) for immunopositivity were tested at 10%, 15% and 20%, respectively. Both the anti-c-erb-B2 primary antibody (clone CB11) and the Dako test were employed to recognize c-erb-B2 protein. Ki67 was measured using the MIB-1 antibody, with ts for positivity at 10%. Patients were required to have a cT>2cm breast cancer. The neoadjuvant chemotherapy included Adriamycin 60mg/m2 or Epirubicin 75mg/m2, in combination with Paclitaxel (175 mg/m2), every 3 weeks for 4 cycles. Bivariate correlations were performed according to Pearson. Results: 38 patients were enrolled until August, 2006. A significant correlation between T-2a and Ki67 was found (r=.598; P<.000); the T-2a positivity rate within Ki67 positive patients was of 90% (10% ts), 86% (15% ts), and 67% (20% ts). No correlation appeared between T-2a and Her-2 labeling indices (r=.150; P=.391); the T-2a positivity rate within Dako +++ patients was 75% (for both 10% and 15% ts) and 50% (for 20% ts). The overall response rate by T-2a overexpression was 61% (10% ts), 70% (15% ts), and 72% (20% ts). Conclusions: We provide a further evidence of the correlation between T-2a and Ki67. We can also generate the hypothesis that a 20% ts for T-2a correlate with a better prediction of response to A-containing chemotherapy; at the same ts, no correlation with Her-2 status was found. No significant financial relationships to disclose.

scholarly journals RNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qian Zhu ◽  
Jinzhou Huang ◽  
Hongyang Huang ◽  
Huan Li ◽  
Peiqiang Yi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cell ◽  
Nuclear Export ◽  
Molecular Mechanisms ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Polymerase Inhibitors

AbstractBRCA1-BARD1 heterodimers act in multiple steps during homologous recombination (HR) to ensure the prompt repair of DNA double strand breaks. Dysfunction of the BRCA1 pathway enhances the therapeutic efficiency of poly-(ADP-ribose) polymerase inhibitors (PARPi) in cancers, but the molecular mechanisms underlying this sensitization to PARPi are not fully understood. Here, we show that cancer cell sensitivity to PARPi is promoted by the ring between ring fingers (RBR) protein RNF19A. We demonstrate that RNF19A suppresses HR by ubiquitinating BARD1, which leads to dissociation of BRCA1-BARD1 complex and exposure of a nuclear export sequence in BARD1 that is otherwise masked by BRCA1, resulting in the export of BARD1 to the cytoplasm. We provide evidence that high RNF19A expression in breast cancer compromises HR and increases sensitivity to PARPi. We propose that RNF19A modulates the cancer cell response to PARPi by negatively regulating the BRCA1-BARD1 complex and inhibiting HR-mediated DNA repair.

scholarly journals DNA Ligase IV Prevents Replication Fork Stalling and Promotes Cellular Proliferation in Triple Negative Breast Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Rashmi R. Joshi ◽  
Sk Imran Ali ◽  
Amanda K. Ashley
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Replication Fork ◽  
Triple Negative ◽  
Double Strand Breaks ◽  
Dna Ligase ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Ligase Iv ◽  
Fork Stalling

DNA damage is a hallmark of cancer, and mutation and misregulation of proteins that maintain genomic fidelity are associated with the development of multiple cancers. DNA double strand breaks are arguably considered the most deleterious type of DNA damage. The nonhomologous end-joining (NHEJ) pathway is one mechanism to repair DNA double strand breaks, and proteins involved in NHEJ may also regulate DNA replication. We previously established that DNA-PKcs, a NHEJ protein, promotes genomic stability and cell viability following cellular exposure to replication stress; we wanted to discern whether another NHEJ protein, DNA ligase IV (Lig4), shares this phenotype. Our investigations focused on triple negative breast cancer cells, as, compared to nonbasal breast cancer, LIG4 is frequently amplified, and an increased gene dose is associated with higher Lig4 expression. We depleted Lig4 using siRNA and confirmed our knockdown by qPCR and western blotting. Cell survival diminished with Lig4 depletion alone, and this was associated with increased replication fork stalling. Checkpoint protein Chk1 activation and dephosphorylation were unchanged in Lig4-depleted cells. Lig4 depletion resulted in sustained DNA-PKcs phosphorylation following hydroxyurea exposure. Understanding the effect of Lig4 on genomic replication and the replication stress response will clarify the biological ramifications of inhibiting Lig4 activity. In addition, Lig4 is an attractive clinical target for directing CRISPR/Cas9-mediated repair towards homology-directed repair and away from NHEJ, thus understanding of how diminishing Lig4 impacts cell biology is critical.

scholarly journals Histone H2AX Promotes Metastatic Progression by Preserving Glycolysis via Hexokinase-2

2021 ◽  
Author(s):  
Yue Liu ◽  
Haojian Li ◽  
Crystal Wilson ◽  
Hui Jen Bai ◽  
Myriem Boufraqech ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Cells ◽  
Ectopic Expression ◽  
Metastatic Breast ◽  
Genomic Stability ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Energetic Metabolism ◽  
Strand Breaks ◽  
Histone H2ax

Abstract Genomic stability is essential for organismal development, cellular homeostasis, and survival. The DNA double-strand breaks are particularly deleterious, creating an environment prone to cellular transformation and oncogenic activation. The histone variant H2AX is an essential component of the nucleosome responsible for initiating the early steps of the DNA repair process. H2AX maintains genomic stability by initiating a signaling cascade that collectively functions to promote DNA double-strand breaks repair. Recent advances have linked genomic stability to energetic metabolism, and alterations in metabolism were found to interfere with genome maintenance. Utilizing genome-wide transcripts profiling to identify differentially-expressed genes involved in energetic metabolism, we compared control and H2AX-deficient metastatic breast cancer cell lines, and found that H2AX loss leads to the repression of key genes regulating glycolysis, with a prominent effect on hexokinase-2 (HK2). These observations are substantiated by evidence that H2AX loss compromises glycolysis, effect which was reversed by ectopic expression of HK2. Utilizing models of experimental metastasis, we found that H2AX silencing halts progression of metastatic breast cancer cells MDA-MB-231. Most interestingly, ectopic expression of HK2 in H2AX-deficient cells restores their metastatic potential. Using multiple publicly available datasets, we found a significantly strong positive correlation between H2AX expression levels in patients with invasive breast cancer, and levels of glycolysis genes, particularly HK2. These observations are consistent with the evidence that high H2AX expression is associated with shorther distant metastasis-free survival. Our findings reveal a role for histone H2AX in controlling the metastatic ability of breast cancer cells via maintenance of HK2-driven glycolysis.

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