Structural insights into inhibitor regulation of the DNA repair protein DNA-PKcs – Nature.com

Posted: January 9, 2022 at 4:44 pm

Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 10711078 (2009).

ADS CAS Article Google Scholar

Lieber, M. R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem. 79, 181211 (2010).

CAS Article Google Scholar

OConnor, M. J. Targeting the DNA damage response in cancer. Mol. Cell 60, 547560 (2015).

Article Google Scholar

Mohiuddin, I. S. & Kang, M. H. DNA-PK as an emerging therapeutic target in cancer. Front. Oncol. 9, 635 (2019).

Article Google Scholar

Sung, P. & Klein, H. Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat. Rev. Mol. Cell Biol. 7, 739750 (2006).

CAS Article Google Scholar

Yang, F., Teves, S. S., Kemp, C. J. & Henikoff, S. Doxorubicin, DNA torsion, and chromatin dynamics. Biochim. Biophys. Acta Rev. Cancer 1845, 8489 (2014).

CAS Article Google Scholar

Davis, A. J., Chen, B. P. C. & Chen, D. J. DNA-PK: a dynamic enzyme in a versatile DSB repair pathway. DNA Repair 17, 2129 (2014).

CAS Article Google Scholar

Chang, H. H. Y., Pannunzio, N. R., Adachi, N. & Lieber, M. F. R. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat. Rev. Mol. Cell Biol. 18, 495506 (2017).

CAS Article Google Scholar

Jette, N. & Lees-Miller, S. P. The DNA-dependent protein kinase: a multifunctional protein kinase with roles in DNA double strand break repair and mitosis. Prog. Biophys. Mol. Biol. 117, 194205 (2015).

CAS Article Google Scholar

Harnor, S. J., Brennan, A. & Cano, C. Targeting DNA-dependent protein kinase for cancer therapy. ChemMedChem 12, 895900 (2017).

CAS Article Google Scholar

Fok, J. H. L. et al. AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity. Nat. Commun. 10, 5065 (2019).

Yang, H. et al. MTOR kinase structure, mechanism and regulation. Nature 497, 217223 (2013).

ADS CAS Article Google Scholar

Chaplin, A. K. et al. Dimers of DNA-PK create a stage for DNA double-strand break repair. Nat. Struct. Mol. Biol. 28, 1319 (2021).

CAS Article Google Scholar

Boulton, S., Kyle, S., Yalintepe, L. & Durkacz, B. W. Wortmannin is a potent inhibitor of DNA double strand break but not single strand break repair in Chinese hamster ovary cells. Carcinogenesis 17, 22852290 (1996).

CAS Article Google Scholar

Walker, E. H. et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol. Cell 6, 909919 (2000).

CAS Article Google Scholar

Hardcastle, I. R. et al. Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach. J. Med. Chem. 48, 78297846 (2005).

CAS Article Google Scholar

Goldberg, F. W. et al. The discovery of 7-methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor. J. Med. Chem. 63, 34613471 (2020).

CAS Article Google Scholar

Zenke, F. T. et al. Pharmacologic inhibitor of DNA-PK, M3814, potentiates radiotherapy and regresses human tumors in mouse models. Mol. Cancer Ther. 19, 10911101 (2020).

CAS Article Google Scholar

van Bussel, M. T. J. et al. A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours. Br. J. Cancer 124, 728735 (2021).

Article Google Scholar

Wise, H. C. et al. Activity of M3814, an oral DNA-PK inhibitor, in combination with topoisomerase II inhibitors in ovarian cancer models. Sci. Rep. 9, 18882 (2019).

ADS CAS Article Google Scholar

Sibanda, B. L., Chirgadze, D. Y., Ascher, D. B. & Blundell, T. L. DNA-PKcs structure suggests an allosteric mechanism modulating DNA double-strand break repair. Science 355, 520524 (2017).

ADS CAS Article Google Scholar

Chen, X. et al. Structure of an activated DNA-PK and its implications for NHEJ. Mol. Cell 81, 801-810 (2021).

CAS Article Google Scholar

Sharif, H. et al. Cryo-EM structure of the DNA-PK holoenzyme. Proc. Natl Acad. Sci. USA 114, 73677372 (2017).

CAS Article Google Scholar

Chen, S. et al. Structural basis of long-range to short-range synaptic transition in NHEJ. Nature https://doi.org/10.1038/s41586-021-03458-7 (2021).

Yin, X., Liu, M., Tian, Y., Wang, J. & Xu, Y. Cryo-EM structure of human DNA-PK holoenzyme. Cell Res. 27, 13411350 (2017).

CAS Article Google Scholar

Chaplin, A. K. et al. Cryo-EM of NHEJ supercomplexes provides insights into DNA repair. Mol. Cell 81, 34003409 (2021).

CAS Article Google Scholar

Davis, A. J., Lee, K. J. & Chen, D. J. The N-terminal region of the DNA-dependent protein kinase catalytic subunit is required for its DNA double-stranded break-mediated activation. J. Biol. Chem. 288, 70377046 (2013).

CAS Article Google Scholar

Graham, T. G. W., Walter, J. C. & Loparo, J. J. Two-stage synapsis of DNA ends during non-homologous end joining. Mol. Cell. 61, 850858 (2016).

Radoux, C. J., Olsson, T. S. G., Pitt, W. R., Groom, C. R. & Blundell, T. L. Identifying interactions that determine fragment binding at protein hotspots. J. Med. Chem. 59, 43144325 (2016).

CAS Article Google Scholar

Hajduk, P. J., Huth, J. R. & Tse, C. Predicting protein druggability. Drug Discov. 10, 16751682 (2005).

CAS Google Scholar

Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16, 101114 (2017).

CAS Article Google Scholar

Sun, X. et al. Protacs: great opportunities for academia and industry. Signal Transduct. Target. Ther. 4, 64 (2019).

Article Google Scholar

Liang, S. et al. Stages, scaffolds and strings in the spatial organisation of non-homologous end joining: insights from X-ray diffraction and cryo-EM. Prog. Biophys. Mol. Biol. 163, 6073 (2020).

Menolfi, D. & Zha, S. ATM, ATR and DNA-PKcs kinasesthe lessons from the mouse models: inhibitiondeletion. Cell Biosci. 10, 8 (2020).

Article Google Scholar

Bokori-Brown, M. et al. Cryo-EM structure of lysenin pore elucidates membrane insertion by an aerolysin family protein. Nat. Commun. 7, 11293 (2016).

ADS CAS Article Google Scholar

Tegunov, D. & Cramer, P. Real-time cryo-electron microscopy data preprocessing with Warp. Nat. Methods 16, 11461152 (2019).

CAS Article Google Scholar

Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. CryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290296 (2017).

CAS Article Google Scholar

Punjani, A., Brubaker, M. A. & Fleet, D. J. Building proteins in a day: efficient 3D molecular structure estimation with electron cryomicroscopy. IEEE Trans. Pattern Anal. Mach. Intell. 39, 706718 (2017).

Article Google Scholar

Rosenthal, P. B. & Henderson, R. Optimal determination of particle orientation, absolute hand, and contrast loss in single-particle electron cryomicroscopy. J. Mol. Biol. 333, 721745 (2003).

CAS Article Google Scholar

Pettersen, E. F. et al. UCSF Chimeraa visualization system for exploratory research and analysis. J. Comput. Chem. 25, 16051612 (2004).

CAS Article Google Scholar

Pettersen, E. F., et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70-82 (2021).

CAS Article Google Scholar

Afonine, P. V. et al. Real-space refinement in PHENIX for cryo-EM and crystallography. Acta Crystallogr. D 74, 531544 (2018).

CAS Article Google Scholar

Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486501 (2010).

CAS Article Google Scholar

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Structural insights into inhibitor regulation of the DNA repair protein DNA-PKcs - Nature.com

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