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Oncogenesis and Metastasis
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Instability occurs because cells evade apoptosis.Cells propagate with DNA damage or are unable to repair damage.Defects in DNA repair pathways.Example: mutations/deletion of BRCA1 and BRCA2 genes (breast, ovarian and prostate cancers).
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
Cells undergo DNA damage during replication and from environmental exposures. Increasing evidence implicates defects in the DNA repair pathway in carcinogenesis, cancer progression, and response to therapy [49]. Damaged cells repair DNA through a system of molecular interactions called the DNA damage response (DDR) pathway. This process allows the integrity of the genome to be maintained; damage to DNA is identified, the cell cycle is halted, and DNA repair is effected [75]. Multiple cellular response mechanisms are involved in the repair of DNA damage, including base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), single strand annealing (SSA), “error free” homologous recombination (HR), and “error prone” non-homologous end joining (NHEJ).
Oncogenes and tumor suppressor genes
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
S. Giordano, S. Corso, P. Conrotto
Defects in genes involved in the control of genetic stability are responsible for certain human diseases associated with an increased susceptibility to cancer. Inactivation of these genes, in fact, leads to genetic instability that, indirectly, promotes growth by causing an increased mutation rate. Targets of this process are oncogenes and tumor suppressor genes (Table 3). Human diseases associated with DNA repair defects are xeroderma pigmentosum, ataxia-teleangectasia, Bloom’s syndrome, Cockayne’s syndrome, Fanconi’s anemia, hereditary nonpolyposis colorectal cancer and hereditary breast cancer.
A mechanistic overview of spinal cord injury, oxidative DNA damage repair and neuroprotective therapies
Published in International Journal of Neuroscience, 2023
Jaspreet Kaur, Aditya Mojumdar
Cells have evolved various DNA repair mechanisms to counteract the effects of various types of lesions (Figure 2). Among others, double-strand breaks (DSB) are the most deleterious forms of damage and to repair such damages there are two canonical pathways Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR) [82]. NHEJ mediates the direct ligation of DNA ends without the requirement for a homologous template and is not restricted to a particular phase of the cell cycle. In contrast, HR-mediated repair only occurs in S and G2 and requires several crucial and complex steps [83,84]. To maintain the efficiency of the repair, several factors play a role in the DNA repair pathway choice [85]. Other than these two conventional double-strand break repair pathways there are alternative pathways such as micro-homology mediated end-joining (MMEJ) and single-strand annealing (SSA). MMEJ is achieved by a minimal end processing to produce cohesive ends followed by ligation, whereas SSA pathway involves end resection to produce single-stranded DNA ends which subsequently anneal and the resulting strands are ligated [86–88].
Clinical value of identifying genes that inhibit hepatocellular carcinomas
Published in Expert Review of Molecular Diagnostics, 2022
Ugo Testa, Elvira Pelosi, Germana Castelli
Alterations of DNA repair genes are frequent in HCC. DNA repair processes are constantly active to limit damage in the DNA structure through several reparative mechanisms implying base excision repair, nucleotide excision repair, mismatch excision repair and homologous recombination. Various gene sets, including checkpoint factors, homologous recombination, mismatch repair, base excision repair, nucleotide excision repair, nonhomologous end-joining and Fanconi anemia; somatic alterations in at least one gene pertaining to DDR pathways are observed in about 20% and 3%, respectively of HCC patients; ATM (6%) and ATR (2.5%) are among the DDR genes most frequently mutated; BRCA1/BRCA2 genes are mutated in about 2.5% of HCC patients [28]. Mezina et al. showed that 11.5% of HCC patients possess pathogenic germline variants: 1.8% with BRCA2, 0.9% with MSH6, 0.9% PMS2, 2.2% FANCA, 1.8% BRIP1 [29]. In another cohort of HCC patients, BRCA2 mutations were observed in about 3% of patients [29]. The presence of DDR gene mutations in HCC patients may have some potential implications for precision treatment.
Ponatinib is a potential therapeutic approach for malignant pleural mesothelioma
Published in Experimental Lung Research, 2021
Yi-Wei Yang, Angelica Marrufo, Jillian Chase, Gavitt A. Woodard, David M. Jablons, Hassan Lemjabbar-Alaoui
Cells are constantly exposed to a number of DNA-damaging factors, including endogenous and environmental factors. Thus, cells regularly rely for their survival on the DNA repair pathways. DNA repair mechanisms play a central role in carcinogenesis and are potential therapeutic targets.26 A growing body of data implicates DNA repair mechanisms in MPM pathogenesis. Several studies have suggested that cAbl is required to properly activate critical elements in the double strand DNA breaks (DSBs) repair pathways, including activation of ATM/ATR and Rad51. Thus, we hypothesized that ponatinib-induced reduction in cell growth might be associated with an amplification of DNA DSBs in MPM cells due to cAbl inhibition. To address this question, we have performed γ-H2AX analysis, a universal pharmacodynamic surrogate marker for DSBs. MSTO-211H cells were treated with ponatinib for 14 h, and a commercially available ELISA-based assay was used to analyze the γH2AX levels in the cells.