THO (белковый комплекс)

Белковый комплекс THO (THOC) это эволюционно консервативный ядерный белковый комплекс, который впервые был найден у дрожжей,[1] а впоследствии у всех эукариот включая человека.[2][3] THO является комплексом, взаимодействующим и с образующейся РНК и с различными факторами, обеспечивающими ядерные функции, необходимые для биогенеза мРНП, и обеспечивающим целостность генома, сплайсинг и экспорт мРНК.[4][5][6]

В клетках человека THOC состоит из шести субъединиц из которых четыре имеют известные аналоги в дрожжах Saccharomyces cerevisiae. Это THOC1 (Hpr1 дрожжей), −2 (Tho2 дрожжей), −3 (Tex3 дрожжей), и −7 (Mft1 дрожжей).[7]

THOC играет важную роль в экспорте РНК из ядра в составе более крупного комплекса называемого TREX (TRanscription-EXport).[8][9] Комплекс THOC/TREX необходим и для участия в транскрипции, и для процессинга РНК и для экспорта РНК из ядра выполняя эти функции совместно с хеликазой и фактором сплайсинга UAP56 осуществляющим роль мостика между комплексом THO и мРНП.[10]

THOC/TREX принимает участие в противодействии накопления повреждений ДНК, вызванных образованием во время транскрипции R-петель.[11][3] В частности THOC способствует стабильности теломер посредством регуляции днРНК TERRA (РНК, которая транскрибируется с теломер и содержит повторяющуюся 6-нуклеотидную последовательность).[12]

Примечания

  1. ↑ Chávez, S., Beilharz, T., Rondón, A. G., Erdjument‐Bromage, H., Tempst, P., Svejstrup, J. Q., ... & Aguilera, A. (2000). A protein complex containing Tho2, Hpr1, Mft1 and a novel protein, Thp2, connects transcription elongation with mitotic recombination in Saccharomyces cerevisiae. The EMBO journal. PMID 11060033 PMC 305808 doi:10.1093/emboj/19.21.5824
  2. ↑ Katahira, J., Senokuchi, K., & Hieda, M. (2020). Human THO maintains the stability of repetitive DNA. Genes to Cells, 25(5), 334-342. PMID 32065701 doi:10.1111/gtc.12760
  3. ↑ 1 2 Salas‐Armenteros, I., Pérez‐Calero, C., Bayona‐Feliu, A., Tumini, E., Luna, R., & Aguilera, A. (2017). Human THO–Sin3A interaction reveals new mechanisms to prevent R‐loops that cause genome instability. The EMBO Journal, 36(23), 3532-3547. PMID 29074626 PMC 5709763 doi:10.15252/embj.201797208
  4. ↑ Luna, R., Rondón, A. G., & Aguilera, A. (2012). New clues to understand the role of THO and other functionally related factors in mRNP biogenesis. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, 1819(6), 514-520. PMID 22207203 doi:10.1016/j.bbagrm.2011.11.012
  5. ↑ Jimeno, S., & Aguilera, A. (2010). The THO complex as a key mRNP biogenesis factor in development and cell differentiation. Journal of biology, 9, 1-3. PMID 20236444 PMC 2871528 doi:10.1186/jbiol217
  6. ↑ Wang, L., Miao, Y. L., Zheng, X., Lackford, B., Zhou, B., Han, L., ... & Hu, G. (2013). The THO complex regulates pluripotency gene mRNA export and controls embryonic stem cell self-renewal and somatic cell reprogramming. Cell stem cell, 13(6), 676-690. PMID 24315442 PMC 3962795 doi:10.1016/j.stem.2013.10.008
  7. ↑ Pühringer, T., Hohmann, U., Fin, L., Pacheco-Fiallos, B., Schellhaas, U., Brennecke, J., & Plaschka, C. (2020). Structure of the human core transcription-export complex reveals a hub for multivalent interactions. Elife, 9, e61503. PMID 33191911 PMC 7744094 doi:10.7554/eLife.61503
  8. ↑ Sträßer, K., Masuda, S., Mason, P., Pfannstiel, J., Oppizzi, M., Rodriguez-Navarro, S., ... & Hurt, E. (2002). TREX is a conserved complex coupling transcription with messenger RNA export. Nature, 417(6886), 304-308. PMID 11979277 doi:10.1038/nature746
  9. ↑ Heath, C. G., Viphakone, N., & Wilson, S. A. (2016). The role of TREX in gene expression and disease. Biochemical Journal, 473(19), 2911-2935. PMID 27679854 PMC 5095910 doi:10.1042/BCJ20160010
  10. ↑ Hohmann, U., Graf, M., Schellhaas, U., Pacheco-Fiallos, B., Fin, L., Riabov-Bassat, D., ... & Plaschka, C. (2024). A molecular switch orchestrates the nuclear export of human messenger RNA. bioRxiv, 2024-03. doi:10.1101/2024.03.24.586400
  11. ↑ Domínguez-Sánchez, M. S., Barroso, S., Gómez-González, B., Luna, R., & Aguilera, A. (2011). Genome instability and transcription elongation impairment in human cells depleted of THO/TREX. PLoS genetics, 7(12), e1002386. PMID 22144908 PMC 3228816 doi:10.1371/journal.pgen.1002386
  12. ↑ Fernandes, R. V., & Lingner, J. (2023). The THO complex counteracts TERRA R-loop-mediated telomere fragility in telomerase+ cells and telomeric recombination in ALT+ cells. Nucleic Acids Research, 51(13), 6702-6722. PMID 37246640 PMC 10359610 doi:10.1093/nar/gkad448

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