Browsing by Subject "DNA damage response (DDR)"

Now showing 1 - 3 of 3
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    Editorial: Targeting DNA repair and the DNA damage response: Beyond the standard PI3 kinase-like kinases
    (Frontiers Media, 2022-09-27) Turchi, John J.; Pawelczak, Katherine S.; Weinfeld, Michael; McHugh, Peter J.; Medicine, School of Medicine
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    Ku-DNA binding inhibitors modulate the DNA damage response in response to DNA double-strand breaks
    (Oxford University Press, 2023-02-06) Mendoza-Munoz, Pamela L.; Gavande, Navnath S.; VanderVere-Carozza, Pamela S.; Pawelczak, Katherine S.; Dynlacht, Joseph R.; Garrett, Joy E.; Turchi, John J.; Medicine, School of Medicine
    The DNA-dependent protein kinase (DNA-PK) plays a critical role in the DNA damage response (DDR) and non-homologous end joining (NHEJ) double-strand break (DSB) repair pathways. Consequently, DNA-PK is a validated therapeutic target for cancer treatment in certain DNA repair-deficient cancers and in combination with ionizing radiation (IR). We have previously reported the discovery and development of a novel class of DNA-PK inhibitors with a unique mechanism of action, blocking the Ku 70/80 heterodimer interaction with DNA. These Ku–DNA binding inhibitors (Ku-DBi's) display nanomolar activity in vitro, inhibit cellular DNA-PK, NHEJ-catalyzed DSB repair and sensitize non-small cell lung cancer (NSCLC) cells to DSB-inducing agents. In this study, we demonstrate that chemical inhibition of the Ku–DNA interaction potentiates the cellular effects of bleomycin and IR via p53 phosphorylation through the activation of the ATM pathway. This response is concomitant with a reduction of DNA-PK catalytic subunit (DNA-PKcs) autophosphorylation at S2056 and a time-dependent increase in H2AX phosphorylation at S139. These results are consistent with Ku-DBi's abrogating DNA-PKcs autophosphorylation to impact DSB repair and DDR signaling through a novel mechanism of action, and thus represent a promising anticancer therapeutic strategy in combination with DNA DSB-inducing agents.
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    Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation
    (American Association for Cancer Research, 2022) Owens, Jake L.; Beketova, Elena; Liu, Sheng; Shen, Qi; Pawar, Jogendra Singh; Asberry, Andrew M.; Yang, Jie; Deng, Xuehong; Elzey, Bennett D.; Ratliff, Timothy L.; Cheng, Liang; Choo, Richard; Citrin, Deborah E.; Polascik, Thomas J.; Wang, Bangchen; Huang, Jiaoti; Li, Chenglong; Wan, Jun; Hu, Chang-Deng; Medical and Molecular Genetics, School of Medicine
    Prostate cancer remains the second leading cause of cancer death among American men. Radiotherapy is a potentially curative treatment for localized prostate cancer, and failure to control localized disease contributes to the majority of prostate cancer deaths. Neuroendocrine differentiation (NED) in prostate cancer, a process by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like (NE-like) cells, is an emerging mechanism of resistance to cancer therapies and contributes to disease progression. NED also occurs in response to treatment to promote the development of treatment-induced neuroendocrine prostate cancer (NEPC), a highly aggressive and terminal stage disease. We previously demonstrated that by mimicking clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces prostate cancer cells to undergo NED in vitro and in vivo. Here, we performed transcriptomic analysis and confirmed that FIR-induced NE-like cells share some features of clinical NEPC, suggesting that FIR-induced NED represents a clinically relevant model. Furthermore, we demonstrated that protein arginine methyltransferase 5 (PRMT5), a master epigenetic regulator of the DNA damage response and a putative oncogene in prostate cancer, along with its cofactors pICln and MEP50, mediate FIR-induced NED. Knockdown of PRMT5, pICln, or MEP50 during FIR-induced NED and sensitized prostate cancer cells to radiation. Significantly, PRMT5 knockdown in prostate cancer xenograft tumors in mice during FIR prevented NED, enhanced tumor killing, significantly reduced and delayed tumor recurrence, and prolonged overall survival. Collectively, our results demonstrate that PRMT5 promotes FIR-induced NED and suggests that targeting PRMT5 may be a novel and effective radiosensitization approach for prostate cancer radiotherapy.