SON protects nascent transcripts from unproductive degradation by counteracting DIP1

Autoři: Mandy Li-Ian Tay aff001;  Jun Wei Pek aff001
Působiště autorů: Temasek Life Sciences Laboratory, Singapore, Singapore aff001;  Department of Biological Sciences, National University of Singapore, Singapore aff002
Vyšlo v časopise: SON protects nascent transcripts from unproductive degradation by counteracting DIP1. PLoS Genet 15(11): e32767. doi:10.1371/journal.pgen.1008498
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008498


Gene expression involves the transcription and splicing of nascent transcripts through the removal of introns. In Drosophila, a double-stranded RNA binding protein Disco-interacting protein 1 (DIP1) targets INE-1 stable intronic sequence RNAs (sisRNAs) for degradation after splicing. How nascent transcripts that also contain INE-1 sequences escape degradation remains unknown. Here we observe that these nascent transcripts can also be bound by DIP1 but the Drosophila homolog of SON (Dsn) protects them from unproductive degradation in ovaries. Dsn localizes to the satellite body where active decay of INE-1 sisRNAs by DIP1 occurs. Dsn is a repressor of DIP1 posttranslational modifications (primarily sumoylation) that are assumed to be required for efficient DIP1 activity. Moreover, the pre-mRNA destabilization caused by Dsn depletion is rescued in DIP1 or Sumo heterozygous mutants, suggesting that Dsn is a negative regulator of DIP1. Our results reveal that under normal circumstances nascent transcripts are susceptible to DIP1-mediated degradation, however intronic sequences are protected by Dsn until intron excision has taken place.

Klíčová slova:

Drosophila melanogaster – Gene expression – Immunoprecipitation – Introns – Messenger RNA – Ovaries – RNA interference – SUMOylation


1. Bresson S, Tollervey D (2018) Surveillance-ready transcription: nuclear RNA decay as a default fate. Open Biol 8.

2. Danin-Kreiselman M, Lee CY, Chanfreau G (2003) RNAse III-mediated degradation of unspliced pre-mRNAs and lariat introns. Mol Cell 11: 1279–1289. doi: 10.1016/s1097-2765(03)00137-0 12769851

3. Kilchert C, Wittmann S, Passoni M, Shah S, Granneman S, et al. (2015) Regulation of mRNA Levels by Decay-Promoting Introns that Recruit the Exosome Specificity Factor Mmi1. Cell Rep 13: 2504–2515. doi: 10.1016/j.celrep.2015.11.026 26670050

4. Chan SN, Pek JW (2019) Stable Intronic Sequence RNAs (sisRNAs): An Expanding Universe. Trends Biochem Sci 44: 258–272. doi: 10.1016/j.tibs.2018.09.016 30391089

5. Osman I, Tay ML, Pek JW (2016) Stable intronic sequence RNAs (sisRNAs): a new layer of gene regulation. Cell Mol Life Sci 73: 3507–3519. doi: 10.1007/s00018-016-2256-4 27147469

6. Pek JW (2018) Stable Intronic Sequence RNAs Engage in Feedback Loops. Trends Genet 34: 330–332. doi: 10.1016/j.tig.2018.01.006 29397203

7. Jia Ng SS, Zheng RT, Osman I, Pek JW (2018) Generation of Drosophila sisRNAs by Independent Transcription from Cognate Introns. iScience 4: 68–75. doi: 10.1016/j.isci.2018.05.010 30240754

8. Pek JW, Okamura K (2015) Regulatory RNAs discovered in unexpected places. WIREs RNA 6: 671–686. doi: 10.1002/wrna.1309 26424536

9. Pek JW, Osman I, Tay ML, Zheng RT (2015) Stable intronic sequence RNAs have possible regulatory roles in Drosophila melanogaster. J Cell Biol 211: 243–251. doi: 10.1083/jcb.201507065 26504165

10. Osman I, Pek JW (2018) A sisRNA/miRNA Axis Prevents Loss of Germline Stem Cells during Starvation in Drosophila. Stem Cell Reports 11: 4–12. doi: 10.1016/j.stemcr.2018.06.002 30008327

11. Tay ML, Pek JW (2017) Maternally Inherited Stable Intronic Sequence RNA Triggers a Self-Reinforcing Feedback Loop during Development. Curr Biol 27: 1062–1067. doi: 10.1016/j.cub.2017.02.040 28343963

12. Locke J, Howard LT, Aippersbach N, Podemski L, Hodgetts RB (1999) The characterization of DINE-1, a short, interspersed repetitive element present on chromosome and in the centric heterochromatin of Drosophila melanogaster. Chromosoma 108: 356–366. doi: 10.1007/s004120050387 10591995

13. Yang HP, Barbash DA (2008) Abundant and species-specific DINE-1 transposable elements in 12 Drosophila genomes. Genome Biol 9: R39. doi: 10.1186/gb-2008-9-2-r39 18291035

14. Yang HP, Hung TL, You TL, Yang TH (2006) Genomewide comparative analysis of the highly abundant transposable element DINE-1 suggests a recent transpositional burst in Drosophila yakuba. Genetics 173: 189–196. doi: 10.1534/genetics.105.051714 16387876

15. Wong JT, Akhbar F, Ng AYE, Tay ML, Loi GJE, et al. (2017) DIP1 modulates stem cell homeostasis in Drosophila through regulation of sisR-1. Nat Commun 8: 759. doi: 10.1038/s41467-017-00684-4 28970471

16. Ng AYE, Peralta KRG, Pek JW (2018) Germline Stem Cell Heterogeneity Supports Homeostasis in Drosophila. Stem Cell Reports 11: 13–21. doi: 10.1016/j.stemcr.2018.05.005 29887366

17. Frolov MV, Benevolenskaya EV, Birchler JA (1998) Regena (Rga), a Drosophila homolog of the global negative transcriptional regulator CDC36 (NOT2) from yeast, modifies gene expression and suppresses position effect variegation. Genetics 148: 317–329. 9475742

18. Temme C, Zaessinger S, Meyer S, Simonelig M, Wahle E (2004) A complex containing the CCR4 and CAF1 proteins is involved in mRNA deadenylation in Drosophila. EMBO J 23: 2862–2871. doi: 10.1038/sj.emboj.7600273 15215893

19. Temme C, Zhang L, Kremmer E, Ihling C, Chartier A, et al. (2010) Subunits of the Drosophila CCR4-NOT complex and their roles in mRNA deadenylation. RNA 16: 1356–1370. doi: 10.1261/rna.2145110 20504953

20. Joanisse DR, Inaguma Y, Tanguay RM (1998) Cloning and developmental expression of a nuclear ubiquitin-conjugating enzyme (DmUbc9) that interacts with small heat shock proteins in Drosophila melanogaster. Biochem Biophys Res Commun 244: 102–109. doi: 10.1006/bbrc.1998.8214 9514881

21. Long X, Griffith LC (2000) Identification and characterization of a SUMO-1 conjugation system that modifies neuronal calcium/calmodulin-dependent protein kinase II in Drosophila melanogaster. J Biol Chem 275: 40765–40776. doi: 10.1074/jbc.M003949200 10995744

22. Smith M, Turki-Judeh W, Courey AJ (2012) SUMOylation in Drosophila Development. Biomolecules 2: 331–349. doi: 10.3390/biom2030331 24970141

23. Lu X, Goke J, Sachs F, Jacques PE, Liang H, et al. (2013) SON connects the splicing-regulatory network with pluripotency in human embryonic stem cells. Nat Cell Biol 15: 1141–1152. doi: 10.1038/ncb2839 24013217

24. Sharma A, Markey M, Torres-Munoz K, Varia S, Kadakia M, et al. (2011) Son maintains accurate splicing for a subset of human pre-mRNAs. J Cell Sci 124: 4286–4298. doi: 10.1242/jcs.092239 22193954

25. Sharma A, Takata H, Shibahara K, Bubulya A, Bubulya PA (2010) Son is essential for nuclear speckle organization and cell cycle progression. Mol Biol Cell 21: 650–663. doi: 10.1091/mbc.E09-02-0126 20053686

26. Fei J, Jadaliha M, Harmon TS, Li ITS, Hua B, et al. (2017) Quantitative analysis of multilayer organization of proteins and RNA in nuclear speckles at super resolution. J Cell Sci 130: 4180–4192. doi: 10.1242/jcs.206854 29133588

27. Lu X, Ng HH, Bubulya PA (2014) The role of SON in splicing, development, and disease. Wiley Interdiscip Rev RNA 5: 637–646. doi: 10.1002/wrna.1235 24789761

28. Kim JH, Baddoo MC, Park EY, Stone JK, Park H, et al. (2016) SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes. Mol Cell 61: 859–873. doi: 10.1016/j.molcel.2016.02.024 26990989

29. Ahn EY, DeKelver RC, Lo MC, Nguyen TA, Matsuura S, et al. (2011) SON controls cell-cycle progression by coordinated regulation of RNA splicing. Mol Cell 42: 185–198. doi: 10.1016/j.molcel.2011.03.014 21504830

30. Kim JH, Shinde DN, Reijnders MRF, Hauser NS, Belmonte RL, et al. (2016) De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome. Am J Hum Genet 99: 711–719. doi: 10.1016/j.ajhg.2016.06.029 27545680

31. Tokita MJ, Braxton AA, Shao Y, Lewis AM, Vincent M, et al. (2016) De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive. Am J Hum Genet 99: 720–727. doi: 10.1016/j.ajhg.2016.06.035 27545676

32. Kaida D, Berg MG, Younis I, Kasim M, Singh LN, et al. (2010) U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468: 664–668. doi: 10.1038/nature09479 20881964

33. Gill G (2004) SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev 18: 2046–2059. doi: 10.1101/gad.1214604 15342487

34. Petrella LN, Smith-Leiker T, Cooley L (2007) The Ovhts polyprotein is cleaved to produce fusome and ring canal proteins required for Drosophila oogenesis. Development 134: 703–712. doi: 10.1242/dev.02766 17215303

35. Pek JW, Kai T (2011) DEAD-box RNA helicase Belle/DDX3 and the RNA interference pathway promote mitotic chromosome segregation. Proc Natl Acad Sci U S A 108: 12007–12012. doi: 10.1073/pnas.1106245108 21730191

Genetika Reprodukční medicína

Článek vyšel v časopise

PLOS Genetics

2019 Číslo 11

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…

Kurzy Doporučená témata Časopisy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se

VIRTUÁLNÍ ČEKÁRNA ČR Jste praktický lékař nebo pediatr? Zapojte se! Jste praktik nebo pediatr? Zapojte se!