5zam

Structural highlights

Disease

[DICER_HUMAN] Defects in DICER1 are a cause of pleuropulmonary blastoma (PPB) [MIM:601200]. PPB is a rare pediatric tumor of the lung that arises during fetal lung development and is often part of an inherited cancer syndrome. PPBs contain both epithelial and mesenchymal cells. Early in tumorigenesis, cysts form in lung airspaces, and these cysts are lined with benign-appearing epithelium. Mesenchymal cells susceptible to malignant transformation reside within the cyst walls and form a dense 'cambium' layer beneath the epithelial lining. In a subset of patients, overgrowth of the mesenchymal cells produces a sarcoma, a transition that is associated with a poorer prognosis.^{[1] [2]} Defects in DICER1 are the cause of goiter multinodular type 1 with or without Sertoli-Leydig cell tumors (MNG1) [MIM:138800]. A common disorder characterized by nodular overgrowth of the thyroid gland. Some individuals may also develop Sertoli-Leydig cell tumors, usually of the ovary.^{[3] [4]} Note=DICER1 mutations have been found in uterine cervix embryonal rhabdomyosarcoma, primitive neuroectodermal tumor, Wilms tumor, pulmonary sequestration and juvenile intestinal polyp (PubMed:21882293). Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in non-epithelial ovarian tumors. These mutations do not abolish DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic (PubMed:22187960).^[5]

Function

[DICER_HUMAN] Required for formation of the RNA induced silencing complex (RISC). Component of the RISC loading complex (RLC), also known as the micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, EIF2C2/AGO2 and TARBP2. Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto EIF2C2/AGO2. EIF2C2/AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. Also cleaves double-stranded RNA to produce short interfering RNAs (siRNAs) which target the selective destruction of complementary RNAs.^{[6] [7] [8] [9] [10] [11] [12] [13] [14] [15]} [TRBP2_HUMAN] Required for formation of the RNA induced silencing complex (RISC). Component of the RISC loading complex (RLC), also known as the micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, EIF2C2/AGO2 and TARBP2. Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto EIF2C2/AGO2. EIF2C2/AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. May also play a role in the production of short interfering RNAs (siRNAs) from double-stranded RNA (dsRNA) by DICER1. Binds to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1, and stimulates translation of TAR-containing RNAs. This is achieved in part at least by binding to and inhibiting EIF2AK2/PKR, thereby reducing phosphorylation and inhibition of EIF2S1/eIF-2-alpha. May also promote translation of TAR-containing RNAs independently of EIF2AK2/PKR.^{[16] [17] [18] [19] [20] [21] [22] [23] [24]}

References

1. ↑ Foulkes WD, Bahubeshi A, Hamel N, Pasini B, Asioli S, Baynam G, Choong CS, Charles A, Frieder RP, Dishop MK, Graf N, Ekim M, Bouron-Dal Soglio D, Arseneau J, Young RH, Sabbaghian N, Srivastava A, Tischkowitz MD, Priest JR. Extending the phenotypes associated with DICER1 mutations. Hum Mutat. 2011 Dec;32(12):1381-4. doi: 10.1002/humu.21600. Epub 2011 Oct 11. PMID:21882293 doi:10.1002/humu.21600
2. ↑ Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, Desruisseau D, Jarzembowski JA, Wikenheiser-Brokamp KA, Suarez BK, Whelan AJ, Williams G, Bracamontes D, Messinger Y, Goodfellow PJ. DICER1 mutations in familial pleuropulmonary blastoma. Science. 2009 Aug 21;325(5943):965. doi: 10.1126/science.1174334. Epub 2009 Jun, 25. PMID:19556464 doi:10.1126/science.1174334
3. ↑ Foulkes WD, Bahubeshi A, Hamel N, Pasini B, Asioli S, Baynam G, Choong CS, Charles A, Frieder RP, Dishop MK, Graf N, Ekim M, Bouron-Dal Soglio D, Arseneau J, Young RH, Sabbaghian N, Srivastava A, Tischkowitz MD, Priest JR. Extending the phenotypes associated with DICER1 mutations. Hum Mutat. 2011 Dec;32(12):1381-4. doi: 10.1002/humu.21600. Epub 2011 Oct 11. PMID:21882293 doi:10.1002/humu.21600
4. ↑ Rio Frio T, Bahubeshi A, Kanellopoulou C, Hamel N, Niedziela M, Sabbaghian N, Pouchet C, Gilbert L, O'Brien PK, Serfas K, Broderick P, Houlston RS, Lesueur F, Bonora E, Muljo S, Schimke RN, Bouron-Dal Soglio D, Arseneau J, Schultz KA, Priest JR, Nguyen VH, Harach HR, Livingston DM, Foulkes WD, Tischkowitz M. DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. JAMA. 2011 Jan 5;305(1):68-77. doi: 10.1001/jama.2010.1910. PMID:21205968 doi:10.1001/jama.2010.1910
5. ↑ Foulkes WD, Bahubeshi A, Hamel N, Pasini B, Asioli S, Baynam G, Choong CS, Charles A, Frieder RP, Dishop MK, Graf N, Ekim M, Bouron-Dal Soglio D, Arseneau J, Young RH, Sabbaghian N, Srivastava A, Tischkowitz MD, Priest JR. Extending the phenotypes associated with DICER1 mutations. Hum Mutat. 2011 Dec;32(12):1381-4. doi: 10.1002/humu.21600. Epub 2011 Oct 11. PMID:21882293 doi:10.1002/humu.21600
6. ↑ Zhang H, Kolb FA, Jaskiewicz L, Westhof E, Filipowicz W. Single processing center models for human Dicer and bacterial RNase III. Cell. 2004 Jul 9;118(1):57-68. PMID:15242644 doi:10.1016/j.cell.2004.06.017
7. ↑ Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 2005 Nov 18;123(4):631-40. Epub 2005 Nov 3. PMID:16271387 doi:10.1016/j.cell.2005.10.022
8. ↑ Meister G, Landthaler M, Peters L, Chen PY, Urlaub H, Luhrmann R, Tuschl T. Identification of novel argonaute-associated proteins. Curr Biol. 2005 Dec 6;15(23):2149-55. Epub 2005 Nov 10. PMID:16289642 doi:10.1016/j.cub.2005.10.048
9. ↑ Haase AD, Jaskiewicz L, Zhang H, Laine S, Sack R, Gatignol A, Filipowicz W. TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO Rep. 2005 Oct;6(10):961-7. PMID:16142218 doi:10.1038/sj.embor.7400509
10. ↑ Maniataki E, Mourelatos Z. A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. Genes Dev. 2005 Dec 15;19(24):2979-90. PMID:16357216 doi:10.1101/gad.1384005
11. ↑ Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, Shiekhattar R. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005 Aug 4;436(7051):740-4. Epub 2005 Jun 22. PMID:15973356 doi:10.1038/nature03868
12. ↑ Lee Y, Hur I, Park SY, Kim YK, Suh MR, Kim VN. The role of PACT in the RNA silencing pathway. EMBO J. 2006 Feb 8;25(3):522-32. Epub 2006 Jan 19. PMID:16424907 doi:10.1038/sj.emboj.7600942
13. ↑ Kok KH, Ng MH, Ching YP, Jin DY. Human TRBP and PACT directly interact with each other and associate with dicer to facilitate the production of small interfering RNA. J Biol Chem. 2007 Jun 15;282(24):17649-57. Epub 2007 Apr 23. PMID:17452327 doi:10.1074/jbc.M611768200
14. ↑ MacRae IJ, Ma E, Zhou M, Robinson CV, Doudna JA. In vitro reconstitution of the human RISC-loading complex. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):512-7. doi: 10.1073/pnas.0710869105., Epub 2008 Jan 4. PMID:18178619 doi:10.1073/pnas.0710869105
15. ↑ Melo SA, Ropero S, Moutinho C, Aaltonen LA, Yamamoto H, Calin GA, Rossi S, Fernandez AF, Carneiro F, Oliveira C, Ferreira B, Liu CG, Villanueva A, Capella G, Schwartz S Jr, Shiekhattar R, Esteller M. A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function. Nat Genet. 2009 Mar;41(3):365-70. doi: 10.1038/ng.317. Epub 2009 Feb 15. PMID:19219043 doi:10.1038/ng.317
16. ↑ Dorin D, Bonnet MC, Bannwarth S, Gatignol A, Meurs EF, Vaquero C. The TAR RNA-binding protein, TRBP, stimulates the expression of TAR-containing RNAs in vitro and in vivo independently of its ability to inhibit the dsRNA-dependent kinase PKR. J Biol Chem. 2003 Feb 14;278(7):4440-8. Epub 2002 Dec 9. PMID:12475984 doi:10.1074/jbc.M208954200
17. ↑ Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 2005 Nov 18;123(4):631-40. Epub 2005 Nov 3. PMID:16271387 doi:10.1016/j.cell.2005.10.022
18. ↑ Haase AD, Jaskiewicz L, Zhang H, Laine S, Sack R, Gatignol A, Filipowicz W. TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO Rep. 2005 Oct;6(10):961-7. PMID:16142218 doi:10.1038/sj.embor.7400509
19. ↑ Maniataki E, Mourelatos Z. A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. Genes Dev. 2005 Dec 15;19(24):2979-90. PMID:16357216 doi:10.1101/gad.1384005
20. ↑ Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, Shiekhattar R. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005 Aug 4;436(7051):740-4. Epub 2005 Jun 22. PMID:15973356 doi:10.1038/nature03868
21. ↑ Lee Y, Hur I, Park SY, Kim YK, Suh MR, Kim VN. The role of PACT in the RNA silencing pathway. EMBO J. 2006 Feb 8;25(3):522-32. Epub 2006 Jan 19. PMID:16424907 doi:10.1038/sj.emboj.7600942
22. ↑ Kok KH, Ng MH, Ching YP, Jin DY. Human TRBP and PACT directly interact with each other and associate with dicer to facilitate the production of small interfering RNA. J Biol Chem. 2007 Jun 15;282(24):17649-57. Epub 2007 Apr 23. PMID:17452327 doi:10.1074/jbc.M611768200
23. ↑ MacRae IJ, Ma E, Zhou M, Robinson CV, Doudna JA. In vitro reconstitution of the human RISC-loading complex. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):512-7. doi: 10.1073/pnas.0710869105., Epub 2008 Jan 4. PMID:18178619 doi:10.1073/pnas.0710869105
24. ↑ Melo SA, Ropero S, Moutinho C, Aaltonen LA, Yamamoto H, Calin GA, Rossi S, Fernandez AF, Carneiro F, Oliveira C, Ferreira B, Liu CG, Villanueva A, Capella G, Schwartz S Jr, Shiekhattar R, Esteller M. A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function. Nat Genet. 2009 Mar;41(3):365-70. doi: 10.1038/ng.317. Epub 2009 Feb 15. PMID:19219043 doi:10.1038/ng.317