Beyond DNA Repair: DNA-PKcs in Tumor Metastasis, Metabolism and Immunity

Yang, Haitang; Yao, Feng; Marti, Thomas; Schmid, Ralph A.; Peng, Ren‐Wang

doi:10.3390/cancers12113389

Cited by 23 publications

(19 citation statements)

References 93 publications

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“…Overexpression of ATM has been associated with lymph node metastasis, while inhibition of ATM has been described to reduce cell migration and invasion [ 61 ]. Similar findings have been obtained for DNA-PK and its inhibition [ 62 , 63 ]. Interestingly, other factors involved in DNA-DSB repair such as the oncogene PP4R1 and Rad51 are also known for facilitating the formation of metastases when upregulated or overexposed and can be regulated with inhibitors [ 64 , 65 ].…”

Section: Discussionsupporting

confidence: 88%

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Faulhaber

Jost

Symank

et al. 2021

Genes

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(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.

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Section: Discussionsupporting

confidence: 88%

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Faulhaber

Jost

Symank

et al. 2021

Genes

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“…DNA-PKcs and Artemis are also required for opening DNA hairpin coding ends during V(D)J recombination and cells lacking DNA-PKcs, Ku, XRCC4 or DNA ligase IV are radiation sensitive and defective in NHEJ and V(D)J recombination (Pannunzio et al, 2018). Recently, additional roles for DNA-PKcs, outside DSB repair have been reported (Yue et al, 2020), including mitosis (Douglas et al, 2014(Douglas et al, , 2020Jette & Lees-Miller, 2015;Lee et al, 2011), transcription (Goodwin et al, 2015;Ju et al, 2006), RNA processing (Shao et al, 2020), metastasis (Goodwin et al, 2015), metabolism (Chung, 2018;Park et al, 2017), the innate immune response (Yang et al, 2020) and HIV replication (Anisenko et al, 2020), but its most well-characterized role is in NHEJ.…”

Section: Repair and Non-repair Functions Of Dna-pkcsmentioning

confidence: 99%

Structural insights into the role of DNA-PK as a master regulator in NHEJ

Chen

Lees‐Miller

et al. 2021

GENOME INSTAB. DIS.

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DNA-dependent protein kinase catalytic subunit DNA-PKcs/PRKDC is the largest serine/threonine protein kinase of the phosphatidyl inositol 3-kinase-like protein kinase (PIKK) family and is the most highly expressed PIKK in human cells. With its DNA-binding partner Ku70/80, DNA-PKcs is required for regulated and efficient repair of ionizing radiation-induced DNA double-strand breaks via the non-homologous end joining (NHEJ) pathway. Loss of DNA-PKcs or other NHEJ factors leads to radiation sensitivity and unrepaired DNA double-strand breaks (DSBs), as well as defects in V(D)J recombination and immune defects. In this review, we highlight the contributions of the late Dr. Carl W. Anderson to the discovery and early characterization of DNA-PK. We furthermore build upon his foundational work to provide recent insights into the structure of NHEJ synaptic complexes, an evolutionarily conserved and functionally important YRPD motif, and the role of DNA-PKcs and its phosphorylation in NHEJ. The combined results identify DNA-PKcs as a master regulator that is activated by its detection of two double-strand DNA ends for a cascade of phosphorylation events that provide specificity and efficiency in assembling the synaptic complex for NHEJ.

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“…ATM germline mutations increase cancer susceptibility, and ATM is frequently mutated in a broad range of sporadic cancers [ 71 ]. Genetic alterations of PRKDC, the gene encoding the catalytic subunit of DNA-PK, are common in several cancer types [ 72 ]. Again, somatic mutations in the ATR gene are exceedingly rare [ 73 ] and no cancer predisposition has been reported for patients with Seckel syndrome or in Seckel mice, even in a p53 mutant background [ 74 ].…”

Section: Atr the Last Hopementioning

confidence: 99%

Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?

Botrugno

Tonon

2021

Cancers

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Multiple Myeloma (MM) is a genetically complex and heterogeneous hematological cancer that remains incurable despite the introduction of novel therapies in the clinic. Sadly, despite efforts spanning several decades, genomic analysis has failed to identify shared genetic aberrations that could be targeted in this disease. Seeking alternative strategies, various efforts have attempted to target and exploit non-oncogene addictions of MM cells, including, for example, proteasome inhibitors. The surprising finding that MM cells present rampant genomic instability has ignited concerted efforts to understand its origin and exploit it for therapeutic purposes. A credible hypothesis, supported by several lines of evidence, suggests that at the root of this phenotype there is intense replicative stress. Here, we review the current understanding of the role of replicative stress in eliciting genomic instability in MM and how MM cells rely on a single protein, Ataxia Telangiectasia-mutated and Rad3-related protein, ATR, to control and survive the ensuing, potentially fatal DNA damage. From this perspective, replicative stress per se represents not only an opportunity for MM cells to increase their evolutionary pool by increasing their genomic heterogeneity, but also a vulnerability that could be leveraged for therapeutic purposes to selectively target MM tumor cells.

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Beyond DNA Repair: DNA-PKcs in Tumor Metastasis, Metabolism and Immunity

Cited by 23 publications

References 93 publications

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Structural insights into the role of DNA-PK as a master regulator in NHEJ

Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?

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