scholarly journals Radiation-induced neuroinflammation – a potential protective role for PARP (poly ADP ribose polymerase) inhibitors?

2022 ◽  
Author(s):  
Rodrigo Gutierrez-Quintana ◽  
David J Walker ◽  
Kaye J Williams ◽  
Duncan M Forster ◽  
Anthony J Chalmers
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Parp Inhibitors ◽  
Protective Role ◽  
Neurocognitive Dysfunction ◽  
Brain Volumes ◽  
Tumour Control ◽  
Large Brain ◽  
Damage Response ◽  
Radiation Induced

Abstract Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbour a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50-90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DNA damage response and subsequent neuroinflammation. PARP inhibitors have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least three compounds being evaluated in clinical trials. We propose that concomitant use of PARP inhibitors could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumour control by enhancing radiosensitivity.

Radiation-induced DNA damage response and resistance in colorectal cancer stem-like cells

2019 ◽  
Vol 95 (6) ◽  
pp. 667-679 ◽  
Author(s):  
Kumari Anuja ◽  
Amit Roy Chowdhury ◽  
Arka Saha ◽  
Souvick Roy ◽  
Arabinda Kumar Rath ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Damage Response ◽  
Radiation Induced

Ionizing radiation-induced DNA damage response identified in marine mussels, Mytilus sp.

2012 ◽  
Vol 168 ◽  
pp. 107-112 ◽  
Author(s):  
Ohoud D. AlAmri ◽  
Andrew B. Cundy ◽  
Yanan Di ◽  
Awadhesh N. Jha ◽  
Jeanette M. Rotchell
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Dna Damage Response ◽  
Damage Response ◽  
Marine Mussels ◽  
Radiation Induced

scholarly journals Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

2019 ◽  
Author(s):  
Elaine Sanij ◽  
Katherine M. Hannan ◽  
Shunfei Yan ◽  
Jiachen Xuan ◽  
Jessica E. Ahern ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Parp Inhibitors ◽  
Rna Polymerase I ◽  
High Grade ◽  
Replication Forks ◽  
Serous Ovarian Cancer ◽  
Damage Response ◽  
Polymerase I

AbstractHigh-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX)in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.

scholarly journals Acetylation dynamics of human nuclear proteins during the ionizing radiation-induced DNA damage response

Cell Cycle ◽  
2013 ◽  
Vol 12 (11) ◽  
pp. 1688-1695 ◽  
Author(s):  
Martin Bennetzen ◽  
Dorthe Larsen ◽  
Christoffel Dinant ◽  
Sugiko Watanabe ◽  
Jiri Bartek ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Dna Damage Response ◽  
Nuclear Proteins ◽  
Damage Response ◽  
Radiation Induced

scholarly journals Resistance to PARP Inhibitors: Lessons from Preclinical Models of BRCA-Associated Cancer

2019 ◽  
Vol 3 (1) ◽  
pp. 235-254 ◽  
Author(s):  
Ewa Gogola ◽  
Sven Rottenberg ◽  
Jos Jonkers
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Parp Inhibitors ◽  
Model Systems ◽  
Basic Knowledge ◽  
Genetic Screens ◽  
Preclinical Models ◽  
Resistant Disease ◽  
Damage Response ◽  
Generation Sequencing

Inhibitors of poly(ADP-ribose) polymerase (PARP) have recently entered the clinic for the treatment of homologous recombination–deficient cancers. Despite the success of this approach, resistance to PARP inhibitors (PARPis) is a clinical hurdle, and it is poorly understood how cancer cells escape the deadly effects of PARPis without restoring BRCA1/2 function. By synergizing the advantages of next-generation sequencing with functional genetic screens in tractable model systems, novel mechanisms providing useful insights into DNA damage response (DDR) have been identified. BRCA1/2 models not only are tools to explore therapy escape mechanisms but also yield basic knowledge about DDR pathways and PARPis’ mechanism of action. Moreover, alterations that render cells resistant to targeted therapies may cause new synthetic dependencies that can be exploited to combat resistant disease.

scholarly journals Regulation of DNA Damage Response and Homologous Recombination Repair by microRNA in Human Cells Exposed to Ionizing Radiation

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1838
Author(s):  
Magdalena Szatkowska ◽  
Renata Krupa
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Ionizing Radiation ◽  
Dna Damage Response ◽  
Cell Response ◽  
Dna Lesions ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Damage Response ◽  
Radiation Induced

Ionizing radiation may be of both artificial and natural origin and causes cellular damage in living organisms. Radioactive isotopes have been used significantly in cancer therapy for many years. The formation of DNA double-strand breaks (DSBs) is the most dangerous effect of ionizing radiation on the cellular level. After irradiation, cells activate a DNA damage response, the molecular path that determines the fate of the cell. As an important element of this, homologous recombination repair is a crucial pathway for the error-free repair of DNA lesions. All components of DNA damage response are regulated by specific microRNAs. MicroRNAs are single-stranded short noncoding RNAs of 20–25 nt in length. They are directly involved in the regulation of gene expression by repressing translation or by cleaving target mRNA. In the present review, we analyze the biological mechanisms by which miRNAs regulate cell response to ionizing radiation-induced double-stranded breaks with an emphasis on DNA repair by homologous recombination, and its main component, the RAD51 recombinase. On the other hand, we discuss the ability of DNA damage response proteins to launch particular miRNA expression and modulate the course of this process. A full understanding of cell response processes to radiation-induced DNA damage will allow us to develop new and more effective methods of ionizing radiation therapy for cancers, and may help to develop methods for preventing the harmful effects of ionizing radiation on healthy organisms.

scholarly journals Polymorphisms of DNA damage response genes in radiation-related and sporadic papillary thyroid carcinoma

2009 ◽  
Vol 16 (2) ◽  
pp. 491-503 ◽  
Author(s):  
Natallia M Akulevich ◽  
Vladimir A Saenko ◽  
Tatiana I Rogounovitch ◽  
Valentina M Drozd ◽  
Eugeny F Lushnikov ◽  
...  
Keyword(s):  
Dna Damage ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Radiation Exposure ◽  
Dna Damage Response ◽  
Papillary Thyroid ◽  
Retrospective Case ◽  
Increased Risk ◽  
Damage Response ◽  
Radiation Induced

Papillary thyroid carcinoma (PTC) etiologically occurs as a radiation-induced or sporadic malignancy. Genetic factors contributing to the susceptibility to either form remain unknown. In this retrospective case–control study, we evaluated possible associations between single-nucleotide polymorphisms (SNPs) in the candidate DNA damage response genes (ATM, XRCC1, TP53, XRCC3, MTF1) and risk of radiation-induced and sporadic PTC. A total of 255 PTC cases (123 Chernobyl radiation-induced and 132 sporadic, all in Caucasians) and 596 healthy controls (198 residents of Chernobyl areas and 398 subjects without history of radiation exposure, all Caucasians) were genotyped. The risk of PTC and SNPs interactions with radiation exposure were assessed by logistic regressions. The ATM G5557A and XRCC1 Arg399Gln polymorphisms, regardless of radiation exposure, associated with a decreased risk of PTC according to the multiplicative and dominant models of inheritance (odds ratio (OR)=0.69, 95% confidence interval (CI) 0.45–0.86 and OR=0.70, 95% CI 0.59–0.93 respectively). The ATM IVS22-77 T>C and TP53 Arg72Pro SNPs interacted with radiation (P=0.04 and P=0.01 respectively). ATM IVS22-77 associated with the increased risk of sporadic PTC (OR=1.84, 95% CI 1.10–3.24) whereas TP53 Arg72Pro correlated with the higher risk of radiogenic PTC (OR=1.80, 95% CI 1.06–2.36). In the analyses of ATM/TP53 (rs1801516/rs664677/rs609429/rs1042522) combinations, the GG/TC/CG/GC genotype strongly associated with radiation-induced PTC (OR=2.10, 95% CI 1.17–3.78). The GG/CC/GG/GG genotype displayed a significantly increased risk for sporadic PTC (OR=3.32, 95% CI 1.57–6.99). The results indicate that polymorphisms of DNA damage response genes may be potential risk modifiers of ionizing radiation-induced or sporadic PTCs.

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