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Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
DNA-PKcs is a kinase that is structurally related to ATM and also responds specifically to DNA damage, in particular to DSBs. Like ATM, DNA-PKcs is unable to act as a sensor of damage itself. This sensor function is carried out by the Ku70/Ku80 complex mentioned previously, which directly binds to the ends of DSBs and recruits DNA-PKcs allowing phosphorylation of H2AX. DNA-PKcs also phosphorylates a number of other target proteins involved in checkpoints and repair.
The Radiobiology and Radiotherapy of HPV-Associated Head and Neck Squamous Cell Carcinoma
Published in Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke, Radiotherapy and Clinical Radiobiology of Head and Neck Cancer, 2018
Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke
Fractionated radiotherapy aims to overcome several mechanisms of radioresistance: hypoxia, tumour repopulation and intrinsic radioresistance. An important signal transduction pathway that is upregulated by radiotherapy is the phosphatidylinositol-3-kinase (PI3-K)/protein kinase B (AKT) cascade. The PI3-K/AKT pathway was found to be involved in all main mechanisms of radioresistance in HNSCC (Bussink, van der Kogel & Kaanders 2008) which implies that targeting this pathway could possibly improve tumour radiosensitivity in aggressive HNC. Radiation-caused DNA double-strand breaks are mostly repaired via non-homologous endjoining (O’Driscoll & Jeggo 2006), a process that is mediated by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) (Lieber et al. 2003). The regulation of DNA-PKcs is dictated by EGFR signalling through the PI3-K/AKT pathway (Toulany et al. 2006), therefore the activation of EGFR enhances DNA repair by the non-homologous endjoining system. Inhibition of this pathway results in an increase of residual DNA double-strand breaks, thus in cellular sensitisation to ionising radiation (Toulany et al. 2005).
TP53 in cancer origin and treatment
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Elena A. Komarova, Peter M. Chumakov, Andrei V. Gudkov
DNA-PK consists of a large catalytic subunit (DNA-PKcs) that is targeted to DNA ends by the Ku heterodimer (polypeptides Ku70 and Ku80) (Dvir et al., 1993; Gottlieb and Jackson, 1993). Binding of DNA-PK to DNA ends in vitro is required in order to phosphorylate a number of different substrates, including TP53 (Anderson and Lees-Miller, 1992; Smith and Jackson, 1999). DNA-PK has been shown to be capable of phosphorylating TP53 on serine-15 and serine-37 in vitro in a DNA-dependent manner (Lees-Miller et al., 1990, 1992).
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
Double stranded DNA breaks can be repaired using nonhomologous end joining repair (NHEJ) or homologous recombination (HR). The repair mechanism used is based on the stability of the end of the DNA breaks [11]. NHEJ directly ligates broken DNA without the need for a homologous template [12]. Because it does not rely on a template, it is able to repair double stranded breaks in any phase of the cell cycle, however, it is also more prone to error than homologous recombination. Homologous recombination is responsible for the reactivation of stalled replication forks and repair of double stranded DNA breaks and inter-strand crosslinks [13]. The repair process occurs in three steps. The broken end of the chromosome if first paired with the homologous region on the sister chromatid. That strand is then invaded to form a Holliday junction, or DNA crossover, which generates a DNA duplex from the two different chromatids [14]. The Holliday junction is then translocated along the DNA and eventually cleaved by endonucleases to again form separate DNA molecules [14]. These two processes are activated by several kinase pathways, ataxia telangiectasia mutated (ATM), ataxia telangiectasia related (ATR), and DNA-PK, which when mutated, result in defective double-strand break repair [15].
The crosstalk between DNA damage response components and DNA-sensing innate immune signaling pathways
Published in International Reviews of Immunology, 2022
Feng Lin, Yan-Dong Tang, Chunfu Zheng
ATM, a sensor of DSBs, which is localized mainly in the nucleus, detects damaged DNA through IκB Kinase α/β to stimulate IRF3-driven IFN-β expression in a U2OS fibrosarcoma stable cell line [38]. However, another study shows that ATM is not required for IFN-I production in response to ISD in early passage MEFs or AT5BIVA cells [35,39]. The different phenomena might result from different cell types or the different physicochemical structures of DNA. Therefore, more studies are needed to examine the exact role of ATM in innate immune responses. DNA-PK is a heterotrimeric protein complex consisting of three proteins Ku70, Ku80, and DNA-PKcs. The key role of NHEJ-mediated DSBs repair also plays critical roles in the DNA sensing innate immune signaling pathways. As a proposed pattern recognition receptor, DNA-PK acts upstream of STING, binds cytoplasmic DNA, and triggers the production of IFN-I, cytokines, and chemokines [40]. A recent study also showed that DNA-PK triggers a STING-independent DNA sensing pathway (SIDSP). DNA-PK initiates SIDSP by detecting exogenous and exposed DNA ends but not damaged DNA or circular plasmid DNA to induce the production of IFN-I [41]. Upon DNA exposure, endogenous Ku70 is transported from the nucleus to the cytoplasm to form a complex with STING, then this Ku70-STING-IRF3-, IRF1-, and IRF7-mediated pathway induces IFN-λ 1 production, which is an IFN-III and has the similar antiviral activity to that of IFN-I [42,43]. Thus, DNA-PK has an important role in DNA sensing innate immune signaling pathways.
Response of breast cancer carcinoma spheroids to combination therapy with radiation and DNA-PK inhibitor: growth arrest without a change in α/β ratio
Published in International Journal of Radiation Biology, 2020
Jing Yu, Ryan Lu, Jessie R. Nedrow, George Sgouros
DNA double-strand breaks (DSBs) caused by XRT lead to chromosomal translocations, genomic instability, and cell death if not repaired (Povirk 2006). The non-homologous end-joining (NHEJ) cell pathway is one of two well-characterized DSB repair pathways. Several core factors, including KU70/80 heterodimer and DNA-PKcs for detecting and tethering DSBs, enzymes such as Artemis and DNA polymerases for processing DNA ends, DNA ligase IV and XRCC4 complex for ligating DNA ends are involved in this pathway (Mahaney et al. 2009; Vignard et al. 2013). DNA-PKcs inhibition decreases DNA repair and increases cells’ radio-sensitivity (O’Connor et al. 2007). NU7441 is a highly potent and selective DNA-PKcs inhibitor which has been shown to sensitize many types of cancers (Ciszewski et al. 2014; Dong et al. 2018; Geng et al. 2019).