Surprisingly, specific inhibitors of the Ku70/80 heterodimer are currently not available. We here describe an in silico, pocket-based drug discovery methodology utilizing the crystal structure of the Ku70/80 heterodimer. We identified a novel putative small molecule binding pocket and selected several potential inhibitors by computational screening.

Ku70 in TSA-induced apoptosis in the CRC cell lines HCT116 and HT29. Ku70 is essential for histone deacetylase inhibitor trichostatin A-induced apoptosis JIN MENG1,2*, FENG ZHANG1*, XU‑TAO ZHANG1, TAO ZHANG3, YU-HUA LI1, LEI FAN1, YANG SUN1, HE‑LONG ZHANG4 and QI‑BING MEI1

2005-04-01 2020-12-01 KU70, an essential gene in the NHEJ pathway, forms a heterodimer with KU80, which has a high affinity to DSB ends and serves as a scaffold for other NHEJ proteins. An inhibitor for KU70/KU80 Ku70 is known to be a repair protein as well as an inhibitor of apoptosis through its association with Bax . The results of the present study have also demonstrated that TSA induced cell death in CRC cells through increasing the acetylation of Ku70, a Bax-binding protein, which therefore promoted Bax release and translocation from the cytoplasm into mitochondria in order to stimulate apoptosis. STL127705 (Compound L) is a Ku 70/80 heterodimer protein inhibitor, inhibits Ku70/80-DNA interaction, with an IC50 of 3.5 μM. STL127705 also inhibits Ku-dependent activation of DNA-PKCS kinase (IC50, 2.5 μM). - Mechanism of Action & Protocol. 2012-06-18 The Ku heterodimer Ku70/80 is required for the NHEJ (non-homologous end-joining) DNA DSB repair pathway.

Ku70 inhibitor

Lastly, we demonstrate that Ku and Aurora B interact following ionizing radiation treatment and that Aurora B inhibition in response to DNA damage is dependent upon Ku70 S155 phosphorylation. Ku70 Ku70 is a DNA repair subunit protein that binds to DNA double-strand break ends and helps repair DNA via the non-homologous end-joining (NHEJ) pathway (Mimori et al., 1986). From: International Review of Cell and Molecular Biology, 2019 Provided herein are methods for identifying and treating subjects having conditions involving aberrant Ku70/80 activity. In particular, the invention relates to small-molecules which function as inhibitors of Ku70/80 protein and the non-homologous end-joining (NHEJ) pathway, and their use as therapeutics for the treatment of cancer and other diseases.

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In order to further validate SMAR1-mediated Ku70 deacetylation via HDAC6, we investigated the effect of HDAC6-specific inhibitor tubacin on the Ku70 deacetylation.

Furthermore, acetyl-Ku70 promoted the dissociation of Ku-70 from BAX, thus promoting BAX-dependent cell apoptosis (Fig. 3e, f).

20 Jul 2007 We found that Ku70, a known DNA repair factor, has a novel function to bind and inhibit Bax (Bcl-2-associated X protein), a key mediator of

They are encoded by the Xrcc5 and Xrcc6 genes, respectively, and are highly abundant in both prokaryotes and eukaryotes. The stability of these proteins depends on each other. 2014-04-11 · This study describes the sensitization mechanism to thermal stress by histone deacetylase inhibitors (HDACIs) in lung cancer cells and shows that Ku70, based on its acetylation status, mediates the protection of lung cancer from hyperthermia (42.5°C, 1-6 hrs). Ku70 regulates apoptosis by sequestering pro-apoptotic Bax. However, its role in thermal stress is not fully understood. The findings 2017-11-24 · Using an siRNA library targeting DSB repair genes, we discover that BRCA2 depletion enhances Chk1-dependent PD-L1 upregulation after X-rays or PARP inhibition. In addition, we show that Ku70/80 The DNA end-joining protein Ku70 is one of several proteins that inhibit apoptosis by sequestering the proapoptotic factor Bax from the mitochondria. However, the molecular mechanism underlying Ku70-dependent inhibition of Bax is not fully understood.

A, dose-dependent effect of four different HDAC inhibitors, including OSU-HDAC42, SAHA, MS-275, and TSA, on histone H3 acetylation (Ac-H3), p21 expression, α-tubulin acetylation, and Ku70 and Ku80 expression. Se hela listan på academic.oup.com Request PDF | Ku70 is essential for histone deacetylase inhibitor trichostatin A-induced apoptosis | It was previously reported that the histone deacetylase inhibitor (HDACI) trichostatin A (TSA Specifically, inhibition of HDAC activity leads to increased acetylation of Ku70, which disrupts its binding to Bax. In turn, Bax is released from Ku70, translocates to mitochondria, and triggers the release of cytochrome c and caspase-dependent apoptosis. 2020-07-22 · Thus, the development of an inhibitor targeting both Ku70 and USP9X, or at least a combination of both Ku70 and USP9X inhibitors, is a feasible approach for further studies.
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Finally, we tested the endogenous role of Ku70 on FOXO4 transcriptional targets by employing RNA interference.

Ku70/Ku80 bindet an freie DNA-Enden und ist in die Reparatur von Doppelstrangbrüchen 25. Juni 2020 Merck hat heute bekannt gegeben, dass die US-amerikanische Zulassungsbehörde Food and Drug Administration (FDA) den 20 Dec 2017 Recruitment of yeast telomerase to telomeres occurs through its Ku and Est1 subunits via independent interactions with telomerase RNA (TLC1) Order for free today.
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Ku70 is essential for histone deacetylase inhibitor trichostatin A-induced apoptosis. [Jin Meng, Feng Zhang, Xu-Tao Zhang, Tao Zhang, Yu-Hua Li, Lei Fan, Yang Sun, He-Long Zhang, Qi-Bing Mei] PMID 25695595

With a KZR-616, a first-in-class selective immunoproteasome inhibitor, is being evaluated in severe and underserved autoimmune diseases.