Volume 2, Issue 2, December 2018, Page: 60-69
Investigation of Novel Functions of KICSTOR Components in the DNA Damage Response
Manideep Chowdary Pachva, Department of Molecular Genetics, Bangor University, Bangor, United Kingdom
Alexander Ryan, Department of Molecular Genetics, Bangor University, Bangor, United Kingdom
Received: Oct. 7, 2018;       Accepted: Nov. 10, 2018;       Published: Dec. 26, 2018
DOI: 10.11648/j.jcebe.20180202.14      View  823      Downloads  118
The mechanistic target of rapamycin complex (mTOR) is an atypical serine/threonine kinase which acts as a global cellular regulator of growth and cell survival in response to environmental cues and is a member of the phosphoinositide 3-kinase (PI3K)-related kinase family. Through the numerous inhibitions and initiations of catabolic and anabolic processes respectively, mTORC1 is also a major promoter for cell-cycle progression. mTORC1 can be activated by growth factors such as insulin as a downstream target of PI3K signaling. It is expressed in all somatic cell types plays vital roles in axonal movement, neuronal plasticity and development in the brain. The aberrant activation of mTORC1 has been implicated as one of the leading causes of Tuberous Sclerosis and Focal Epilepsies. Constitutively active mutations in mTOR complex subunits and their upstream signalling proteins have also been documented in over 30% of Cancers, such as the recently recognised links to prostate and colon cancer. Some PI3K/mTOR inhibitors have also been shown to potently inhibit DNA damage responses in non-small cell lung cancer (NSCLC) cell lines suggesting mTOR plays a key role in DNA damage response (DDR) mechanisms. This review focuses on delineating the mTOR pathway, mechanism of mTOR inhibitors and their possible role in inhibiting the DDR mechanism.
To cite this article
Manideep Chowdary Pachva, Alexander Ryan, Investigation of Novel Functions of KICSTOR Components in the DNA Damage Response, Journal of Chemical, Environmental and Biological Engineering. Vol. 2, No. 2, 2018, pp. 60-69. doi: 10.11648/j.jcebe.20180202.14
Copyright © 2018 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Hanahan, D. & Weinberg, R. A. 2011. Hallmarks of cancer: the next generation. Cell. 144 (5). pp. 646-674.
Cheng, N., Chytil, A., Shyr, Y., Joly, A. & Moses, H. L. 2008. Transforming growth factor-beta signaling-deficient fibroblasts enhance hepatocyte growth factor signaling in mammary carcinoma cells to promotescattering and invasion. Molecular cancer research: MCR. 6 (10). pp. 1521-1533.
O'Reilly, K. E., Rojo, F., She, Q. B., Solit, D., Mills, G. B., Smith, D., Lane, H., Hofmann, F., Hicklin, D. J., Ludwig, D. L., Baselga, J. & Rosen, N. 2006. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer research. 66 (3). pp. 1500-1508.
Torgovnick, A. & Schumacher, B. 2015. DNA repair mechanisms in cancer development and therapy. Frontiers in genetics. 6 pp. 157.
DeBont, R. & van Larebeke, N. 2004. Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis. 19 (3). pp. 169-185.
Lindahl, T. & Barnes, D. E. 2000. Repair of endogenous DNA damage. Cold Spring Harbor symposia on quantitative biology. 65 pp. 127-133.
West, S. C. 2003. Molecular views of recombination proteins and their control. Nature reviews Molecular cell biology. 4 (6). pp. 435-445.
Ciccia, A. & Elledge, S. J. 2010. The DNA damage response: making it safe to play with knives. Molecular cell. 40 (2). pp. 179-204.
Guo, F. 2014. Mtor-Fanconi Anemia DNA Damage Repair Pathway in Cancer. Journal of oncobiomarkers. 2 (2). pp. 5.
Hoeijmakers, J. H. 2009. DNA damage, aging, and cancer. New England Journal of Medicine. 361 (15). pp. 1475-1485.
Caldecott, K. W. 2008. Single-strand break repair and genetic disease. Nature Reviews Genetics. 9 (8). pp. 619-631.
Kuo, L. J. & Yang, L. X. 2008. Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In vivo (Athens, Greece). 22 (3). pp. 305-309.
Meek, K., Dang, V. & Lees-Miller, S. P. 2008. DNA-PK: the means to justify the ends? Advances in Immunology. 99 pp. 33-58.
Shrivastav, M., De Haro, L. P. & Nickoloff, J. A. 2008. Regulation of DNA double-strand break repair pathway choice. Cell research. 18 (1). pp. 134-147.
Jeggo, P. A. & Lobrich, M. 2005. Artemis links ATM to double strand break rejoining. Cell cycle. 4 (3). pp. 359-362.
Laplante, M. & Sabatini, D. M. 2012. mTOR signaling in growth control and disease. Cell. 149 (2). pp. 274-293.
Cafferkey, R., Young, P. R., McLaughlin, M. M., Bergsma, D. J., Koltin, Y., Sathe, G. M., Faucette, L., Eng, W. K., Johnson, R. K. & Livi, G. P. 1993. Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3- kinase and VPS34 abrogate rapamycin cytotoxicity. Molecular and cellular biology. 13 (10). pp. 6012-6023.
Brown, E. J., Albers, M. W., Shin, T. B., Ichikawa, K., Keith, C. T., Lane, W. S. & Schreiber S. L. 1994. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 369 (6483). pp. 756.
Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S. H. 1994. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell. 78 (1). pp. 35-43.
Sabers, C. J., Martin, M. M., Brunn, G. J., Williams, J. M., Dumont, F. J., Wiederrecht, G. & Abraham, R. T. 1995. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. Journal of Biological Chemistry. 270 (2). pp. 815- 822.
Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A. L., Nada, S. & Sabatini, D. M. 2010. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 141 (2). pp. 290-303.
Kim, D., Sarbassov, D. D., Ali, S. M., King, J. E., Latek, R. R., Erdjument-Bromage, H., Tempst, P. & Sabatini, D. M. 2002. mTOR interacts with raptor to form a nutrient- sensitive complex that signals to the cell growth machinery. Cell. 110 (2). pp. 163-175.
Fang, Y., Vilella-Bach, M., Bachmann, R., Flanigan, A. & Chen, J. 2001. Phosphatidic acid- mediated mitogenic activation of mTOR signaling. Science (New York, N. Y.). 294 (5548). pp. 1942-1945.
Yip, C. K., Murata, K., Walz, T., Sabatini, D. M. & Kang, S. A. 2010. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Molecular cell. 38 (5). pp. 768-774.
Baldassari, S., Licchetta, L., Tinuper, P., Bisulli, F. & Pippucci, T. 2016. GATOR1 complex: the common genetic actor in focal epilepsies. Journalofmedical genetics. 53 (8). pp. 503-510.
Mao, Z., Bozzella, M., Seluanov, A. & Gorbunova, V. 2008. DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells. Cell cycle. 7 (18). pp. 2902-2906.
Shimobayashi, M. & Hall, M. N. 2016. Multiple amino acid sensing inputs to mTORC1. Cell research. 26 (1). pp. 7-20.
Durán, R. V., Oppliger, W., Robitaille, A. M., Heiserich, L., Skendaj, R., Gottlieb, E. & Hall, M. N. 2012. Glutaminolysis activates Rag-mTORC1 signaling. Molecular cell. 47 (3). pp. 349-358.
Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M. & Sabatini, D. M. 2013. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science (New York, N. Y.). 340 (6136). pp. 1100-1106.
Miki, D., Ochi, H., Hayes, C. N., Abe, H., Yoshima, T., Aikata, H., Ikeda, K., Kumada, H., Toyota, J. & Morizono, T. 2011. Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nature genetics. 43 (8). pp. 797-800.
Seng, T. J., Ichimura, K., Liu, L., Tingby, O., Pearson, D. M. & Collins, V. P. 2005. Complex chromosome 22 rearrangements in astrocytic tumors identified using microsatellite and chromosome 22 tile path array analysis. Genes, Chromosomes and Cancer. 43 (2). pp. 181-193.
Chantranupong, L., Wolfson, R. L., Orozco, J. M., Saxton, R. A., Scaria, S. M., Bar- Peled, L., Spooner, E., Isasa, M., Gygi, S. P. & Sabatini, D. M. 2014. The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell reports. 9 (1). pp. 1-8.
Wang, S., Tsun, Z. Y., Wolfson, R. L., Shen, K., Wyant, G. A., Plovanich, M. E., Yuan, E. D., Jones, T. D., Chantranupong, L., Comb, W., Wang, T., Bar-Peled, L., Zoncu, R., Straub, C., Kim, C., Park, J., Sabatini, B. L. & Sabatini, D. M. 2015. Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science (New York, N. Y.). 347 (6218). pp. 188-194.
Wolfson, R. L., Chantranupong, L., Wyant, G. A., Gu, X., Orozco, J. M., Shen, K., Condon, K. J., Petri, S., Kedir, J. & Scaria, S. M. 2017. KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature. 543 (7645). pp. 438-442.
Peng, M., Yin, N. & Li, M. O. 2017. SZT2 dictates GATOR control of mTORC1 signalling. Nature.
Frankel, W. N., Yang, Y., Mahaffey, C. L., Beyer, B. J. & O'Brien, T. P. 2009. Szt2, a novel gene for seizure threshold in mice. Genes, Brain and Behavior. 8 (5). pp. 568-576.
Baple, E. L., Maroofian, R., Chioza, B. A., Izadi, M., Cross, H. E., Al-Turki, S., Barwick, K., Skrzypiec, A., Pawlak, R. & Wagner, K. 2014. Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures. The American Journal of Human Genetics. 94 (1). pp. 87-94.
Ma, X. M. & Blenis, J. 2009. Molecular mechanisms of mTOR-mediated translational control. Nature reviews Molecular cell biology. 10 (5). pp. 307-318.
Holler, M., Grottke, A., Mueck, K., Manes, J., Jücker, M., Rodemann, H. P. & Toulany, M. 2016. Dual Targeting of Akt and mTORC1 Impairs Repair of DNA Double- Strand Breaks and Increases Radiation Sensitivity of Human Tumor Cells. PloS one. 11 (5). pp. e0154745.
Mukherjee, B., Tomimatsu, N., Amancherla, K., Camacho, C. V., Pichamoorthy, N. & Burma, S. 2012. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM-and DNA-PKCs-mediated DNA damage responses. Neoplasia. 14 (1). pp. 34IN5-43IN8.
Dominick, G., Bowman, J., Li, X., Miller, R. A. & Garcia, G. G. 2017. mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice. Aging cell. 16 (1). pp. 52-60.
Belin, B. J., Lee, T. & Mullins, R. D. 2015. DNA damage induces nuclear actin filament assembly by Formin -2 and Spire-(1/2) that promotes efficient DNA repair. [corrected. eLife. 4 pp. e07735.
Fell, V. L. & Schild-Poulter, C. 2012. Ku regulates signaling to DNA damage response pathways through the Ku70 von Willebrand A domain. Molecular and cellular biology. 32 (1). pp. 76.
Browse journals by subject