# FBL

## Overview
Fibrillarin, the protein encoded by the FBL gene, is a crucial nucleolar protein primarily involved in the biogenesis of ribosomes, the cellular structures responsible for protein synthesis. The FBL gene encodes for fibrillarin, which is integral to the 2'-O-methylation of precursor ribosomal RNA, a modification essential for the proper assembly and function of ribosomes. Fibrillarin is a component of a ribonucleoprotein complex that includes other proteins and is directed by small nucleolar RNAs to methylate ribose moieties at specific sites. This protein also plays a role in the methylation of histone H2A, influencing transcription and translation processes independent of traditional initiation factors. Structurally, fibrillarin contains an N-terminal glycine-arginine-rich (GAR) domain, a central RNA-binding domain, and a C-terminal domain characteristic of methyltransferases, underscoring its multifunctional enzymatic roles within the cell (Newton2003Fibrillarin; Decle-Carrasco2023Current).

## Function
Fibrillarin, encoded by the FBL gene, is a nucleolar protein that plays a critical role in the biogenesis of ribosomes, which are essential for protein synthesis in cells. This protein is involved in the 2'-O-methylation of precursor ribosomal RNA (pre-rRNA), a modification crucial for the proper processing and assembly of ribosomes (Nguyen2022Low; Decle-Carrasco2023Current). Fibrillarin is part of a ribonucleoprotein complex that includes other proteins such as Nop56p, Nop58p, Snu13p, and is responsible for the methylation of ribose moieties at the 2'-hydroxyl group of rRNA, directed by guide small nucleolar RNAs (snoRNAs) (Newton2003Fibrillarin).

In addition to its role in ribosome assembly, Fibrillarin influences rRNA transcription by methylation of histone H2A, affecting translation initiation from internal ribosome entry site (IRES) elements independently of translation initiation factors (Dimitrova2019RNA). This suggests that Fibrillarin's activity is crucial for the normal function of ribosomes and thus for protein synthesis in cells. The protein's structure includes an N-terminal GAR domain, a central RNA-binding domain, and a C-terminal domain similar to methyltransferases, indicating its role in these enzymatic processes (Newton2003Fibrillarin). Fibrillarin's localization and function are also influenced by its interaction with phosphoinositides, which may facilitate necessary phase separations for pre-rRNA processing (Decle-Carrasco2023Current).

## Clinical Significance
Mutations and alterations in the expression of the FBL gene, which encodes the fibrillarin protein, have significant clinical implications, particularly in the context of various cancers and potentially other diseases linked to cell cycle dysregulation and ribosome biogenesis. In breast cancer, overexpression of FBL is associated with increased cell proliferation and resistance to chemotherapy drugs like doxorubicin, suggesting a protective effect against such treatments. High levels of FBL mRNA in breast cancer tumors correlate with poor prognosis, including lower relapse-free and breast cancer-specific survival rates, indicating its role as an independent marker of poor outcome (Marcel2013p53). Similarly, in hepatocellular carcinoma (HCC), high FBL expression is significantly linked to larger tumor diameters, advanced TNM stages, and poorer prognoses, including shorter overall survival and disease-free survival times (Zhang2020Increased). These findings underscore the potential of FBL as a therapeutic target in oncology, given its involvement in crucial cellular processes like ribosome biogenesis and protein synthesis, which are pivotal in cancer progression. The regulatory mechanisms, including methylation of its promoter, further highlight the complexity of FBL's role in tumorigenesis and its potential as a biomarker for aggressive cancer phenotypes (Zhang2020Increased).

## Interactions
Fibrillarin (FBL) is involved in multiple protein-protein and protein-nucleic acid interactions that are crucial for its function in ribosomal RNA (rRNA) processing and ribosome biogenesis. FBL is a core component of small nucleolar ribonucleoproteins (snoRNPs), interacting with small nucleolar RNAs (snoRNAs) to direct site-specific 2'-O-methylation of rRNA, a process essential for the maturation of rRNA (Shubina2016Nucleolar). It forms complexes with other snoRNP core proteins such as Nop56, Nop58, and the 15.5 kDa protein, which are crucial for the nucleolar localization and stability of snoRNAs (Rodriguez‐Corona2015Fibrillarin).

In the context of viral infections, FBL interacts with the HIV-1 Tat protein and U3 snoRNA, impairing pre-rRNA processing and thus inhibiting ribosomal biogenesis (Decle-Carrasco2023Current). Additionally, during Henipavirus infection, FBL interacts with the HeV matrix protein, which is crucial for the virus's exploitation of the host's ribosomal machinery (Decle-Carrasco2023Current).

FBL also interacts with histone H2A, playing a role in the methylation of histone H2A at glutamine 104 (H2AQ104me), which is significant for rRNA synthesis and overall transcription processes. This interaction is regulated by the acetylation state of FBL, where deacetylation by SIRT7 enhances its binding capability (Iyer-Bierhoff2018SIRT7-Dependent).

These interactions underline the multifunctional role of FBL in cellular growth, viral infection response, and gene expression regulation through its involvement in critical methylation processes.


## References


[1. (Iyer-Bierhoff2018SIRT7-Dependent) Aishwarya Iyer-Bierhoff, Nicolai Krogh, Peter Tessarz, Thomas Ruppert, Henrik Nielsen, and Ingrid Grummt. Sirt7-dependent deacetylation of fibrillarin controls histone h2a methylation and rrna synthesis during the cell cycle. Cell Reports, 25(11):2946-2954.e5, December 2018. URL: http://dx.doi.org/10.1016/j.celrep.2018.11.051, doi:10.1016/j.celrep.2018.11.051. (70 citations) 10.1016/j.celrep.2018.11.051](https://doi.org/10.1016/j.celrep.2018.11.051)

[2. (Zhang2020Increased) Jing Zhang, Gang Yang, Qiang Li, and Fei Xie. Increased fibrillarin expression is associated with tumor progression and an unfavorable prognosis in hepatocellular carcinoma. Oncology Letters, December 2020. URL: http://dx.doi.org/10.3892/ol.2020.12353, doi:10.3892/ol.2020.12353. (12 citations) 10.3892/ol.2020.12353](https://doi.org/10.3892/ol.2020.12353)

[3. (Rodriguez‐Corona2015Fibrillarin) Ulises Rodriguez‐Corona, Margarita Sobol, Luis Carlos Rodriguez‐Zapata, Pavel Hozak, and Enrique Castano. Fibrillarin from archaea to human. Biology of the Cell, 107(6):159–174, April 2015. URL: http://dx.doi.org/10.1111/boc.201400077, doi:10.1111/boc.201400077. (93 citations) 10.1111/boc.201400077](https://doi.org/10.1111/boc.201400077)

[4. (Nguyen2022Low) Flora Nguyen Van Long, Audrey Lardy-Cleaud, Dimitri Carène, Caroline Rossoni, Frédéric Catez, Paul Rollet, Nathalie Pion, Déborah Monchiet, Agathe Dolbeau, Marjorie Martin, Valentin Simioni, Susan Bray, Doris Le Beherec, Fernanda Mosele, Ibrahim Bouakka, Amélie Colombe-Vermorel, Laetitia Odeyer, Alexandra Diot, Lee B. Jordan, Alastair M. Thompson, Françoise Jamen, Thierry Dubois, Sylvie Chabaud, Stefan Michiels, Isabelle Treilleux, Jean-Christophe Bourdon, David Pérol, Alain Puisieux, Fabrice André, Jean-Jacques Diaz, and Virginie Marcel. Low level of fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer. BMC Cancer, May 2022. URL: http://dx.doi.org/10.1186/s12885-022-09552-x, doi:10.1186/s12885-022-09552-x. (11 citations) 10.1186/s12885-022-09552-x](https://doi.org/10.1186/s12885-022-09552-x)

[5. (Marcel2013p53) Virginie Marcel, Sandra E. Ghayad, Stéphane Belin, Gabriel Therizols, Anne-Pierre Morel, Eduardo Solano-Gonzàlez, Julie A. Vendrell, Sabine Hacot, Hichem C. Mertani, Marie Alexandra Albaret, Jean-Christophe Bourdon, Lee Jordan, Alastair Thompson, Yasmine Tafer, Rong Cong, Philippe Bouvet, Jean-Christophe Saurin, Frédéric Catez, Anne-Catherine Prats, Alain Puisieux, and Jean-Jacques Diaz. P53 acts as a safeguard of translational control by regulating fibrillarin and rrna methylation in cancer. Cancer Cell, 24(3):318–330, September 2013. URL: http://dx.doi.org/10.1016/j.ccr.2013.08.013, doi:10.1016/j.ccr.2013.08.013. (307 citations) 10.1016/j.ccr.2013.08.013](https://doi.org/10.1016/j.ccr.2013.08.013)

[6. (Dimitrova2019RNA) Dilyana G. Dimitrova, Laure Teysset, and Clément Carré. Rna 2’-o-methylation (nm) modification in human diseases. Genes, 10(2):117, February 2019. URL: http://dx.doi.org/10.3390/genes10020117, doi:10.3390/genes10020117. (125 citations) 10.3390/genes10020117](https://doi.org/10.3390/genes10020117)

[7. (Newton2003Fibrillarin) Kathryn Newton, Elisabeth Petfalski, David Tollervey, and Javier F. Cáceres. Fibrillarin is essential for early development and required for accumulation of an intron-encoded small nucleolar rna in the mouse. Molecular and Cellular Biology, 23(23):8519–8527, December 2003. URL: http://dx.doi.org/10.1128/mcb.23.23.8519-8527.2003, doi:10.1128/mcb.23.23.8519-8527.2003. (89 citations) 10.1128/mcb.23.23.8519-8527.2003](https://doi.org/10.1128/mcb.23.23.8519-8527.2003)

[8. (Shubina2016Nucleolar) M. Y. Shubina, Y. R. Musinova, and E. V. Sheval. Nucleolar methyltransferase fibrillarin: evolution of structure and functions. Biochemistry (Moscow), 81(9):941–950, September 2016. URL: http://dx.doi.org/10.1134/s0006297916090030, doi:10.1134/s0006297916090030. (35 citations) 10.1134/s0006297916090030](https://doi.org/10.1134/s0006297916090030)

[9. (Decle-Carrasco2023Current) Stefano Decle-Carrasco, Alma Laura Rodríguez-Piña, Luis Carlos Rodríguez-Zapata, and Enrique Castano. Current research on viral proteins that interact with fibrillarin. Molecular Biology Reports, 50(5):4631–4643, March 2023. URL: http://dx.doi.org/10.1007/s11033-023-08343-2, doi:10.1007/s11033-023-08343-2. (3 citations) 10.1007/s11033-023-08343-2](https://doi.org/10.1007/s11033-023-08343-2)