Browsing by Author "Nasrallah, Nawar Al"

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    Discovery and development of novel DNA-PK inhibitors by targeting the unique Ku–DNA interaction
    (Oxford Academic, 2020-11) Gavande, Navnath S; VanderVere-Carozza, Pamela S; Pawelczak, Katherine S; Mendoza-Munoz, Pamela; Vernon, Tyler L; Hanakahi, Leslyn A; Summerlin, Matthew; Dynlacht, Joseph R; Farmer, Annabelle H; Sears, Catherine R; Nasrallah, Nawar Al; Garrett, Joy; Turchi, John J; Medicine, School of Medicine
    DNA-dependent protein kinase (DNA-PK) plays a critical role in the non-homologous end joining (NHEJ) repair pathway and the DNA damage response (DDR). DNA-PK has therefore been pursued for the development of anti-cancer therapeutics in combination with ionizing radiation (IR). We report the discovery of a new class of DNA-PK inhibitors that act via a novel mechanism of action, inhibition of the Ku-DNA interaction. We have developed a series of highly potent and specific Ku-DNA binding inhibitors (Ku-DBi's) that block the Ku-DNA interaction and inhibit DNA-PK kinase activity. Ku-DBi's directly interact with the Ku and inhibit in vitro NHEJ, cellular NHEJ, and potentiate the cellular activity of radiomimetic agents and IR. Analysis of Ku-null cells demonstrates that Ku-DBi's cellular activity is a direct result of Ku inhibition, as Ku-null cells are insensitive to Ku-DBi's. The utility of Ku-DBi's was also revealed in a CRISPR gene-editing model where we demonstrate that the efficiency of gene insertion events was increased in cells pre-treated with Ku-DBi's, consistent with inhibition of NHEJ and activation of homologous recombination to facilitate gene insertion. These data demonstrate the discovery and application of new series of compounds that modulate DNA repair pathways via a unique mechanism of action.
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    Xeroderma Pigmentosum Complementation Group C (XPC): Emerging Roles in Non-Dermatologic Malignancies
    (Frontiers Media, 2022-04-21) Nasrallah, Nawar Al; Wiese, Benjamin M.; Sears, Catherine R.; Medicine, School of Medicine
    Xeroderma pigmentosum complementation group C (XPC) is a DNA damage recognition protein essential for initiation of global-genomic nucleotide excision repair (GG-NER). Humans carrying germline mutations in the XPC gene exhibit strong susceptibility to skin cancer due to defective removal via GG-NER of genotoxic, solar UV-induced dipyrimidine photoproducts. However, XPC is increasingly recognized as important for protection against non-dermatologic cancers, not only through its role in GG-NER, but also by participating in other DNA repair pathways, in the DNA damage response and in transcriptional regulation. Additionally, XPC expression levels and polymorphisms likely impact development and may serve as predictive and therapeutic biomarkers in a number of these non-dermatologic cancers. Here we review the existing literature, focusing on the role of XPC in non-dermatologic cancer development, progression, and treatment response, and highlight possible future applications of XPC as a prognostic and therapeutic biomarker.