Lysosomes Support DNA Replication: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Joanna Merchut-Maya.

Lysosomes, acidic, membrane-bound organelles, are not only the core of the cellular recycling machinery, but they also serve as signaling hubs regulating various metabolic pathways. Lysosomes maintain energy homeostasis and provide pivotal substrates for anabolic processes, such as DNA replication. Every time the cell divides, its genome needs to be correctly duplicated; therefore, DNA replication requires rigorous regulation. Challenges that negatively affect DNA synthesis, such as nucleotide imbalance, result in replication stress with severe consequences for genome integrity. The lysosomal complex mTORC1 is directly involved in the synthesis of purines and pyrimidines to support DNA replication.

  • lysosomes
  • autophagy
  • mTORC1
  • DNA synthesis
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References

  1. Davidson, S.M.; Vander Heiden, M.G. Critical functions of the lysosome in cancer biology. Annu. Rev. Pharmacol. Toxicol. 2017, 57, 481–507.
  2. Luzio, J.P.; Pryor, P.R.; Bright, N.A. Lysosomes: Fusion and function. Nat. Rev. Mol. Cell Biol. 2007, 8, 622–632.
  3. Winchester, B.G. Lysosomal membrane proteins. Eur. J. Paediatr. Neurol. 2001, 5 (Suppl. A), 11–19.
  4. Woychik, N.A.; Cardelli, J.A.; Dimond, R.L. A conformationally altered precursor to the lysosomal enzyme alpha-mannosidase accumulates in the endoplasmic reticulum in a mutant strain of Dictyostelium discoideum. J. Biol. Chem. 1986, 261, 9595–9602.
  5. Galluzzi, L.; Pietrocola, F.; Bravo-San Pedro, J.M.; Amaravadi, R.K.; Baehrecke, E.H.; Cecconi, F.; Codogno, P.; Debnath, J.; Gewirtz, D.A.; Karantza, V.; et al. Autophagy in malignant transformation and cancer progression. EMBO J. 2015, 34, 856–880.
  6. Diao, J.; Liu, R.; Rong, Y.; Zhao, M.; Zhang, J.; Lai, Y.; Zhou, Q.; Wilz, L.M.; Li, J.; Vivona, S.; et al. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature 2015, 520, 563–566.
  7. Audano, M.; Schneider, A.; Mitro, N. Mitochondria, lysosomes, and dysfunction: Their meaning in neurodegeneration. J. Neurochem. 2018, 147, 291–309.
  8. Rothman, J.H.; Yamashiro, C.T.; Raymond, C.K.; Kane, P.M.; Stevens, T.H. Acidification of the lysosome-like vacuole and the vacuolar H+-ATPase are deficient in two yeast mutants that fail to sort vacuolar proteins. J. Cell Biol. 1989, 109, 93–100.
  9. Bastos, A.L.; Moura Nunes, J.F.; Vigario, J.D.; Nunes Petisca, J.L.; Terrinha, A.M. The effect of lysosome permeability changes on DNA synthesis and mitosis of cells growing in vitro. Z. Krebsforsch. 1967, 69, 1–9.
  10. Comings, O.E.; Kovacs, B.W.; Avelino, E.; Harris, D.C. Mechanisms of chromosome banding. V. Quinacrine banding. Chromosoma 1975, 50, 111–114.
  11. Saxton, R.A.; Sabatini, D.M. mTOR Signaling in Growth, Metabolism, and Disease. Cell 2017, 168, 960–976.
  12. 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.; et al. Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 2015, 347, 188–194.
  13. Kim, E.; Goraksha-Hicks, P.; Li, L.; Neufeld, T.P.; Guan, K.L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 2008, 10, 935–945.
  14. Sancak, Y.; Peterson, T.R.; Shaul, Y.D.; Lindquist, R.A.; Thoreen, C.C.; Bar-Peled, L.; Sabatini, D.M. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008, 320, 1496–1501.
  15. Hosokawa, N.; Hara, T.; Kaizuka, T.; Kishi, C.; Takamura, A.; Miura, Y.; Iemura, S.; Natsume, T.; Takehana, K.; Yamada, N.; et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 2009, 20, 1981–1991.
  16. Gwinn, D.M.; Shackelford, D.B.; Egan, D.F.; Mihaylova, M.M.; Mery, A.; Vasquez, D.S.; Turk, B.E.; Shaw, R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 2008, 30, 214–226.
  17. Herzig, S.; Shaw, R.J. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 2018, 19, 121–135.
  18. Kalender, A.; Selvaraj, A.; Kim, S.Y.; Gulati, P.; Brule, S.; Viollet, B.; Kemp, B.E.; Bardeesy, N.; Dennis, P.; Schlager, J.J.; et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010, 11, 390–401.
  19. Lin, S.C.; Hardie, D.G. AMPK: Sensing glucose as well as cellular energy status. Cell Metab. 2018, 27, 299–313.
  20. Chavez, J.A.; Roach, W.G.; Keller, S.R.; Lane, W.S.; Lienhard, G.E. Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation. J. Biol. Chem. 2008, 283, 9187–9195.
  21. Ben-Sahra, I.; Hoxhaj, G.; Ricoult, S.J.H.; Asara, J.M.; Manning, B.D. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 2016, 351, 728–733.
  22. Hoxhaj, G.; Hughes-Hallett, J.; Timson, R.C.; Ilagan, E.; Yuan, M.; Asara, J.M.; Ben-Sahra, I.; Manning, B.D. The mTORC1 Signaling Network Senses Changes in Cellular Purine Nucleotide Levels. Cell Rep. 2017, 21, 1331–1346.
  23. Emmanuel, N.; Ragunathan, S.; Shan, Q.; Wang, F.; Giannakou, A.; Huser, N.; Jin, G.; Myers, J.; Abraham, R.T.; Unsal-Kacmaz, K. Purine Nucleotide Availability Regulates mTORC1 Activity through the Rheb GTPase. Cell Rep. 2017, 19, 2665–2680.
  24. French, J.B.; Jones, S.A.; Deng, H.; Pedley, A.M.; Kim, D.; Chan, C.Y.; Hu, H.; Pugh, R.J.; Zhao, H.; Zhang, Y.; et al. Spatial colocalization and functional link of purinosomes with mitochondria. Science 2016, 351, 733–737.
  25. Ben-Sahra, I.; Howell, J.J.; Asara, J.M.; Manning, B.D. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 2013, 339, 1323–1328.
  26. Martel, R.R.; Klicius, J.; Galet, S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can. J. Physiol. Pharmacol. 1977, 55, 48–51.
  27. Kahan, B.D.; Chang, J.Y.; Sehgal, S.N. Preclinical evaluation of a new potent immunosuppressive agent, rapamycin. Transplantation 1991, 52, 185–191.
  28. Ilagan, E.; Manning, B.D. Emerging role of mTOR in the response to cancer therapeutics. Trends Cancer 2016, 2, 241–251.
  29. Pollizzi, K.N.; Powell, J.D. Regulation of T cells by mTOR: The known knowns and the known unknowns. Trends Immunol. 2015, 36, 13–20.
  30. Vanzo, R.; Bartkova, J.; Merchut-Maya, J.M.; Hall, A.; Bouchal, J.; Dyrskjot, L.; Frankel, L.B.; Gorgoulis, V.; Maya-Mendoza, A.; Jaattela, M.; et al. Autophagy role(s) in response to oncogenes and DNA replication stress. Cell Death Differ. 2020, 27, 1134–1153.
  31. Maya-Mendoza, A.; Moudry, P.; Merchut-Maya, J.M.; Lee, M.; Strauss, R.; Bartek, J. High speed of fork progression induces DNA replication stress and genomic instability. Nature 2018, 559, 279–284.
  32. Matsushime, H.; Quelle, D.E.; Shurtleff, S.A.; Shibuya, M.; Sherr, C.J.; Kato, J.Y. D-type cyclin-dependent kinase activity in mammalian cells. Mol. Cell. Biol. 1994, 14, 2066–2076.
  33. Peters, G. The D-type cyclins and their role in tumorigenesis. J. Cell Sci. Suppl. 1994, 18, 89–96.
  34. Weinberg, R.A. E2F and cell proliferation: A world turned upside down. Cell 1996, 85, 457–459.
  35. Hashemolhosseini, S.; Nagamine, Y.; Morley, S.J.; Desrivieres, S.; Mercep, L.; Ferrari, S. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J. Biol. Chem. 1998, 273, 14424–14429.
  36. Diffley, J.F. Regulation of early events in chromosome replication. Curr. Biol. 2004, 14, R778–R786.
  37. Siddiqui, K.; On, K.F.; Diffley, J.F. Regulating DNA replication in eukarya. Cold Spring Harb. Perspect. Biol. 2013, 5.
  38. Akerman, I.; Kasaai, B.; Bazarova, A.; Sang, P.B.; Peiffer, I.; Artufel, M.; Derelle, R.; Smith, G.; Rodriguez-Martinez, M.; Romano, M.; et al. A predictable conserved DNA base composition signature defines human core DNA replication origins. Nat. Commun. 2020, 11, 4826.
  39. Yeeles, J.T.; Deegan, T.D.; Janska, A.; Early, A.; Diffley, J.F. Regulated eukaryotic DNA replication origin firing with purified proteins. Nature 2015, 519, 431–435.
  40. Galluzzi, L.; Baehrecke, E.H.; Ballabio, A.; Boya, P.; Bravo-San Pedro, J.M.; Cecconi, F.; Choi, A.M.; Chu, C.T.; Codogno, P.; Colombo, M.I.; et al. Molecular definitions of autophagy and related processes. EMBO J. 2017, 36, 1811–1836.
  41. Mizushima, N. A brief history of autophagy from cell biology to physiology and disease. Nat. Cell Biol. 2018, 20, 521–527.
  42. Kaushik, S.; Cuervo, A.M. Chaperone-mediated autophagy: A unique way to enter the lysosome world. Trends Cell Biol. 2012, 22, 407–417.
  43. Stricher, F.; Macri, C.; Ruff, M.; Muller, S. HSPA8/HSC70 chaperone protein: Structure, function, and chemical targeting. Autophagy 2013, 9, 1937–1954.
  44. Li, X.; He, S.; Ma, B. Autophagy and autophagy-related proteins in cancer. Mol. Cancer 2020, 19, 12.
  45. Kang, H.M.; Lee, J.S.; Kim, M.S.; Lee, Y.H.; Jung, J.H.; Hagiwara, A.; Zhou, B.; Lee, J.S.; Jeong, C.B. Genome-wide identification of 99 autophagy-related (Atg) genes in the monogonont rotifer Brachionus spp. and transcriptional modulation in response to cadmium. Aquat. Toxicol. 2018, 201, 73–82.
  46. Karanasios, E.; Stapleton, E.; Manifava, M.; Kaizuka, T.; Mizushima, N.; Walker, S.A.; Ktistakis, N.T. Dynamic association of the ULK1 complex with omegasomes during autophagy induction. J. Cell Sci. 2013, 126, 5224–5238.
  47. Dooley, H.C.; Razi, M.; Polson, H.E.; Girardin, S.E.; Wilson, M.I.; Tooze, S.A. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol. Cell 2014, 55, 238–252.
  48. Tsukamoto, S.; Kuma, A.; Murakami, M.; Kishi, C.; Yamamoto, A.; Mizushima, N. Autophagy is essential for preimplantation development of mouse embryos. Science 2008, 321, 117–120.
  49. Komatsu, M.; Waguri, S.; Ueno, T.; Iwata, J.; Murata, S.; Tanida, I.; Ezaki, J.; Mizushima, N.; Ohsumi, Y.; Uchiyama, Y.; et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 2005, 169, 425–434.
  50. Levine, B.; Kroemer, G. Autophagy in the pathogenesis of disease. Cell 2008, 132, 27–42.
  51. Poole, L.P.; Macleod, K.F. Mitophagy in tumorigenesis and metastasis. Cell. Mol. Life Sci. 2021.
  52. Liu, L.; Tian, Z.; Zhang, Y.; Liu, P.; Xin, Z.; Zhao, Y.; Li, Y.; Miao, S.; Shi, J.; Chen, Z.; et al. Ligand-based discovery of small molecules suppressing cancer cell proliferation via autophagic flux inhibition. J. Mol. Med. 2020, 98, 1573–1589.
  53. Fitzwalter, B.E.; Thorburn, A. Recent insights into cell death and autophagy. FEBS J. 2015, 282, 4279–4288.
  54. Karantza-Wadsworth, V.; Patel, S.; Kravchuk, O.; Chen, G.; Mathew, R.; Jin, S.; White, E. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007, 21, 1621–1635.
  55. Young, A.R.; Narita, M.; Ferreira, M.; Kirschner, K.; Sadaie, M.; Darot, J.F.; Tavare, S.; Arakawa, S.; Shimizu, S.; Watt, F.M.; et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 2009, 23, 798–803.
  56. Galanos, P.; Vougas, K.; Walter, D.; Polyzos, A.; Maya-Mendoza, A.; Haagensen, E.J.; Kokkalis, A.; Roumelioti, F.M.; Gagos, S.; Tzetis, M.; et al. Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing. Nat. Cell Biol. 2016, 18, 777–789.
  57. Filippi-Chiela, E.C.; Bueno e Silva, M.M.; Thome, M.P.; Lenz, G. Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage. Autophagy 2015, 11, 1099–1113.
  58. Levy, J.M.M.; Towers, C.G.; Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer 2017, 17, 528–542.
  59. Gillespie, D.A.; Ryan, K.M. Autophagy is critically required for DNA repair by homologous recombination. Mol. Cell. Oncol. 2016, 3, e1030538.
  60. Dyavaiah, M.; Rooney, J.P.; Chittur, S.V.; Lin, Q.; Begley, T.J. Autophagy-dependent regulation of the DNA damage response protein ribonucleotide reductase 1. Mol. Cancer Res. 2011, 9, 462–475.
  61. Bester, A.C.; Roniger, M.; Oren, Y.S.; Im, M.M.; Sarni, D.; Chaoat, M.; Bensimon, A.; Zamir, G.; Shewach, D.S.; Kerem, B. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 2011, 145, 435–446.
  62. Filomeni, G.; De Zio, D.; Cecconi, F. Oxidative stress and autophagy: The clash between damage and metabolic needs. Cell Death. Differ. 2015, 22, 377–388.
  63. Sullivan, L.B.; Gui, D.Y.; Hosios, A.M.; Bush, L.N.; Freinkman, E.; Vander Heiden, M.G. Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. Cell 2015, 162, 552–563.
  64. Roberts, P.; Moshitch-Moshkovitz, S.; Kvam, E.; O’Toole, E.; Winey, M.; Goldfarb, D.S. Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae. Mol. Biol. Cell 2003, 14, 129–141.
  65. Dou, Z.; Xu, C.; Donahue, G.; Shimi, T.; Pan, J.A.; Zhu, J.; Ivanov, A.; Capell, B.C.; Drake, A.M.; Shah, P.P.; et al. Autophagy mediates degradation of nuclear lamina. Nature 2015, 527, 105–109.
  66. Erenpreisa, J.; Huna, A.; Salmina, K.; Jackson, T.R.; Cragg, M.S. Macroautophagy-aided elimination of chromatin: Sorting of waste, sorting of fate? Autophagy 2012, 8, 1877–1881.
  67. Wilhelm, T.; Olziersky, A.M.; Harry, D.; De Sousa, F.; Vassal, H.; Eskat, A.; Meraldi, P. Mild replication stress causes chromosome mis-segregation via premature centriole disengagement. Nat. Commun. 2019, 10, 3585.
  68. Krupina, K.; Goginashvili, A.; Cleveland, D.W. Causes and consequences of micronuclei. Curr. Opin. Cell Biol. 2021, 70, 91–99.
  69. Rello-Varona, S.; Lissa, D.; Shen, S.; Niso-Santano, M.; Senovilla, L.; Marino, G.; Vitale, I.; Jemaa, M.; Harper, F.; Pierron, G.; et al. Autophagic removal of micronuclei. Cell Cycle 2012, 11, 170–176.
  70. Iadevaia, V.; Liu, R.; Proud, C.G. mTORC1 signaling controls multiple steps in ribosome biogenesis. Semin. Cell Dev. Biol. 2014, 36, 113–120.
  71. Deshpande, R.A.; Shankar, V. Ribonucleases from T2 family. Crit. Rev. Microbiol. 2002, 28, 79–122.
  72. Evans, C.J.; Aguilera, R.J. DNase II: Genes, enzymes and function. Gene 2003, 322, 1–15.
  73. Hase, K.; Fujiwara, Y.; Kikuchi, H.; Aizawa, S.; Hakuno, F.; Takahashi, S.; Wada, K.; Kabuta, T. RNautophagy/DNautophagy possesses selectivity for RNA/DNA substrates. Nucleic Acids Res. 2015, 43, 6439–6449.
  74. Huang, H.; Kawamata, T.; Horie, T.; Tsugawa, H.; Nakayama, Y.; Ohsumi, Y.; Fukusaki, E. Bulk RNA degradation by nitrogen starvation-induced autophagy in yeast. EMBO J. 2015, 34, 154–168.
  75. Fujiwara, Y.; Kikuchi, H.; Aizawa, S.; Furuta, A.; Hatanaka, Y.; Konya, C.; Uchida, K.; Wada, K.; Kabuta, T. Direct uptake and degradation of DNA by lysosomes. Autophagy 2013, 9, 1167–1171.
  76. Lan, Y.Y.; Londono, D.; Bouley, R.; Rooney, M.S.; Hacohen, N. Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. Cell Rep. 2014, 9, 180–192.
  77. Coquel, F.; Neumayer, C.; Lin, Y.L.; Pasero, P. SAMHD1 and the innate immune response to cytosolic DNA during DNA replication. Curr. Opin. Immunol. 2019, 56, 24–30.
  78. Zhao, Z.; Qin, P.; Huang, Y.W. Lysosomal ion channels involved in cellular entry and uncoating of enveloped viruses: Implications for therapeutic strategies against SARS-CoV-2. Cell Calcium 2021, 94, 102360.
  79. Miao, G.; Zhao, H.; Li, Y.; Ji, M.; Chen, Y.; Shi, Y.; Bi, Y.; Wang, P.; Zhang, H. ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation. Dev. Cell 2021, 56, 427–442.e425.
  80. Yang, C.; Ko, B.; Hensley, C.T.; Jiang, L.; Wasti, A.T.; Kim, J.; Sudderth, J.; Calvaruso, M.A.; Lumata, L.; Mitsche, M.; et al. Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol. Cell 2014, 56, 414–424.
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