# U2AF1

## Overview
U2AF1, or U2 small nuclear RNA auxiliary factor 1, is a gene that encodes a protein essential for the splicing of pre-messenger RNA (pre-mRNA) in human cells. The protein, also known as U2AF35, plays a pivotal role in the recognition and binding of the polypyrimidine tract at the 3' splice site of pre-mRNA, which is crucial for the assembly of the spliceosome and the subsequent removal of introns from pre-mRNA. This process is vital for the correct processing of pre-mRNA into mature mRNA, which is then translated into proteins that perform various cellular functions. U2AF1 is also involved in mRNA translation regulation and alternative splicing, which adds a layer of complexity to its role in gene expression and cellular dynamics. Mutations in the U2AF1 gene are associated with various forms of cancer and other diseases, highlighting its significance in maintaining cellular health and function (Palangat2019The; Fei2016Wild-type).

## Structure
The U2AF1 protein, also known as U2AF35, is characterized by a complex molecular structure essential for its role in pre-mRNA splicing. The protein includes two CCCH-type zinc knuckles, ZnK1 and ZnK2, which are crucial for RNA binding and are involved in recognizing and binding RNA, influencing splice site selection and splicing outcomes (Jenkins2017Splicing). These zinc knuckles surround the U2AF2 heterodimerization motif (UHM), which is integral to the protein's function (Jenkins2017Splicing).

The U2AF1 protein also features a U2AF homology motif (UHM) flanked by zinc knuckles. The UHM shares structural similarities with the RNA Recognition Motif (RRM), exhibiting a βαββαβ topology, which is an α/β-sandwich arranged in a four-strand, antiparallel β-sheet packed against two α-helices. However, unlike typical RRMs that bind RNA, the U2AF1 UHM is adapted primarily for protein-protein interactions, particularly with ULM (U2AF Ligand Motif) domains of other proteins (Loerch2016Unmasking).

Additionally, U2AF1 undergoes alternative splicing to produce two isoforms, U2AF35a and U2AF35b, which arise from tandem 67-nucleotide exons. These exons encode parts of the U2AF-homology motif (UHM), contributing to the diversity of interactions and functional nuances of the protein (Kralovicova2016Alternative).

Mutations in U2AF1, such as the S34F mutation, can alter these RNA binding characteristics, which is relevant in the context of myelodysplastic syndromes (MDS), highlighting the importance of its structural integrity in disease (Loerch2016Unmasking).

## Function
U2AF1 (U2 small nuclear RNA auxiliary factor 1) is a critical component of the spliceosome, the complex responsible for the removal of introns from pre-mRNA in human cells. This gene encodes a protein that specifically recognizes and binds to the polypyrimidine tract at the 3' splice site of pre-mRNA, facilitating the recruitment of other spliceosomal components necessary for the splicing process. This interaction is essential for the accurate and efficient processing of pre-mRNA into mature mRNA, which subsequently translates into proteins vital for various cellular functions (Palangat2019The; Fei2016Wild-type).

In addition to its canonical role in splicing, U2AF1 also participates in the regulation of mRNA translation. It has been shown to bind directly to mRNA in the cytoplasm, particularly at the 5'-UTR near the start codon, where it can repress translation. This binding is specific to sequences that include a polypyrimidine tract followed by an 'AG' dinucleotide, indicating a regulatory role during translation initiation (Palangat2019The).

The proper function of U2AF1 in splice site selection and mRNA translation is crucial for maintaining normal cellular functions and processes. Disruptions in U2AF1 function, such as mutations, can lead to differential splicing patterns associated with various diseases, including cancer (Fei2016Wild-type).

## Clinical Significance
Mutations in the U2AF1 gene are significantly associated with various hematologic malignancies and solid tumors. In myelodysplastic syndromes (MDS), mutations such as S34F and Q157P are prevalent, affecting the gene's role in pre-mRNA splicing and leading to altered hematopoiesis. These mutations are linked to poorer overall survival and a higher risk of progression to acute myeloid leukemia (AML) (Wu2013Clinical; Yip2017The). U2AF1 mutations are also found in acute myeloid leukemia, where they contribute to the disease's pathogenesis by inducing aberrant splicing patterns (Shirai2015Mutant).

In solid tumors, U2AF1 mutations are implicated in lung cancers, particularly lung adenocarcinoma, where the S34F mutation is noted, although its functional significance remains to be fully understood (Esfahani2019Functional). The gene's mutations are also identified in prostate and ovarian cancers, suggesting a broader role in cancer pathogenesis beyond hematologic disorders (Nian2023U2AF1).

Furthermore, U2AF1 mutations have been observed in other cancers such as head and neck squamous cell carcinoma, uterine corpus endometrial carcinoma, bladder urothelial carcinoma, breast adenocarcinoma, and colorectal carcinoma, indicating a general role in cancer development (Shirai2015Mutant). These mutations not only affect the splicing of genes but also impact critical pathways like DNA damage repair and NF-κB signaling, contributing to the complexity of the disease phenotypes associated with U2AF1 alterations (Nian2023U2AF1).

## Interactions
U2AF1, as part of the U2 auxiliary factor heterodimer with U2AF2, plays a crucial role in pre-mRNA splicing by recognizing and binding to the polypyrimidine tract and the AG dinucleotide at the 3' splice site of introns. This interaction is essential for the recruitment of the spliceosome components necessary for splicing regulation (Whisenant2015The). U2AF1 also interacts with other proteins through its U2AF Homology Motif (UHM), which engages in protein-protein interactions crucial for splicing. For instance, U2AF1's UHM binds to the U2AF Ligand Motif (ULM) of SF1 and SF3b155, which is important for the specificity of splicing events (Loerch2016Unmasking).

Additionally, U2AF1 forms a heterodimer with U2AF2, which is involved in various cellular compartments, indicating dynamic interactions across different cellular environments (Palangat2019The). The protein also participates in interactions influenced by its mutation status; for example, the S34F mutation in U2AF1 alters its RNA binding characteristics, impacting RNA splicing and possibly overall gene expression (Esfahani2019Functional).

These interactions highlight U2AF1's role not only in the canonical splicing process but also in the regulation of alternative splicing and gene expression, underscoring its importance in cellular function and the potential implications of its dysregulation in diseases such as cancer.


## References


[1. (Loerch2016Unmasking) Sarah Loerch and Clara L. Kielkopf. Unmasking the u2af homology motif family: a bona fide protein–protein interaction motif in disguise. RNA, 22(12):1795–1807, November 2016. URL: http://dx.doi.org/10.1261/rna.057950.116, doi:10.1261/rna.057950.116. (53 citations) 10.1261/rna.057950.116](https://doi.org/10.1261/rna.057950.116)

[2. (Wu2013Clinical) Shang-Ju Wu, Jih-Luh Tang, Chien-Ting Lin, Yuan-Yeh Kuo, Li-Yu Li, Mei-Hsuan Tseng, Chi-Fei Huang, Yen-Jun Lai, Fen-Yu Lee, Ming-Chih Liu, Chia-Wen Liu, Hsin-An Hou, Chien-Yuan Chen, Wen-Chien Chou, Ming Yao, Shang-Yi Huang, Bor-Sheng Ko, Woei Tsay, and Hwei-Fang Tien. Clinical implications of u2af1 mutation in patients with myelodysplastic syndrome and its stability during disease progression. American Journal of Hematology, September 2013. URL: http://dx.doi.org/10.1002/ajh.23541, doi:10.1002/ajh.23541. (68 citations) 10.1002/ajh.23541](https://doi.org/10.1002/ajh.23541)

[3. (Whisenant2015The) Thomas C. Whisenant, Eigen R. Peralta, Lauren D. Aarreberg, Nina J. Gao, Steven R. Head, Phillip Ordoukhanian, Jamie R. Williamson, and Daniel R. Salomon. The activation-induced assembly of an rna/protein interactome centered on the splicing factor u2af2 regulates gene expression in human cd4 t cells. PLOS ONE, 10(12):e0144409, December 2015. URL: http://dx.doi.org/10.1371/journal.pone.0144409, doi:10.1371/journal.pone.0144409. (19 citations) 10.1371/journal.pone.0144409](https://doi.org/10.1371/journal.pone.0144409)

[4. (Jenkins2017Splicing) Jermaine L. Jenkins and Clara L. Kielkopf. Splicing factor mutations in myelodysplasias: insights from spliceosome structures. Trends in Genetics, 33(5):336–348, May 2017. URL: http://dx.doi.org/10.1016/j.tig.2017.03.001, doi:10.1016/j.tig.2017.03.001. (60 citations) 10.1016/j.tig.2017.03.001](https://doi.org/10.1016/j.tig.2017.03.001)

[5. (Nian2023U2AF1) Qing Nian, Yihui Li, Jingwei Li, Liyun Zhao, Fernando Lima, Jinhao Zeng, Rongxing Liu, and Zhijun Ye. U2af1 in various neoplastic diseases and relevant targeted therapies for malignant cancers with complex mutations (review). Oncology Reports, November 2023. URL: http://dx.doi.org/10.3892/or.2023.8664, doi:10.3892/or.2023.8664. (0 citations) 10.3892/or.2023.8664](https://doi.org/10.3892/or.2023.8664)

[6. (Yip2017The) Bon Ham Yip, Violetta Steeples, Emmanouela Repapi, Richard N. Armstrong, Miriam Llorian, Swagata Roy, Jacqueline Shaw, Hamid Dolatshad, Stephen Taylor, Amit Verma, Matthias Bartenstein, Paresh Vyas, Nicholas C.P. Cross, Luca Malcovati, Mario Cazzola, Eva Hellström-Lindberg, Seishi Ogawa, Christopher W.J. Smith, Andrea Pellagatti, and Jacqueline Boultwood. The u2af1s34f mutation induces lineage-specific splicing alterations in myelodysplastic syndromes. Journal of Clinical Investigation, 127(6):2206–2221, April 2017. URL: http://dx.doi.org/10.1172/jci91363, doi:10.1172/jci91363. (62 citations) 10.1172/jci91363](https://doi.org/10.1172/jci91363)

[7. (Shirai2015Mutant) Cara Lunn Shirai, James N. Ley, Brian S. White, Sanghyun Kim, Justin Tibbitts, Jin Shao, Matthew Ndonwi, Brian Wadugu, Eric J. Duncavage, Theresa Okeyo-Owuor, Tuoen Liu, Malachi Griffith, Sean McGrath, Vincent Magrini, Robert S. Fulton, Catrina Fronick, Michelle O’Laughlin, Timothy A. Graubert, and Matthew J. Walter. Mutant u2af1 expression alters hematopoiesis and pre-mrna splicing in vivo. Cancer Cell, 27(5):631–643, May 2015. URL: http://dx.doi.org/10.1016/j.ccell.2015.04.008, doi:10.1016/j.ccell.2015.04.008. (323 citations) 10.1016/j.ccell.2015.04.008](https://doi.org/10.1016/j.ccell.2015.04.008)

[8. (Esfahani2019Functional) Mohammad S. Esfahani, Luke J. Lee, Young-Jun Jeon, Ryan A. Flynn, Henning Stehr, Angela B. Hui, Noriko Ishisoko, Eric Kildebeck, Aaron M. Newman, Scott V. Bratman, Matthew H. Porteus, Howard Y. Chang, Ash A. Alizadeh, and Maximilian Diehn. Functional significance of u2af1 s34f mutations in lung adenocarcinomas. Nature Communications, December 2019. URL: http://dx.doi.org/10.1038/s41467-019-13392-y, doi:10.1038/s41467-019-13392-y. (36 citations) 10.1038/s41467-019-13392-y](https://doi.org/10.1038/s41467-019-13392-y)

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[10. (Palangat2019The) Murali Palangat, Dimitrios G. Anastasakis, Dennis Liang Fei, Katherine E. Lindblad, Robert Bradley, Christopher S. Hourigan, Markus Hafner, and Daniel R. Larson. The splicing factor u2af1 contributes to cancer progression through a noncanonical role in translation regulation. Genes & Development, 33(9–10):482–497, March 2019. URL: http://dx.doi.org/10.1101/gad.319590.118, doi:10.1101/gad.319590.118. (79 citations) 10.1101/gad.319590.118](https://doi.org/10.1101/gad.319590.118)

[11. (Kralovicova2016Alternative) Jana Kralovicova and Igor Vorechovsky. Alternative splicing ofu2af1reveals a shared repression mechanism for duplicated exons. Nucleic Acids Research, 45(1):417–434, August 2016. URL: http://dx.doi.org/10.1093/nar/gkw733, doi:10.1093/nar/gkw733. (14 citations) 10.1093/nar/gkw733](https://doi.org/10.1093/nar/gkw733)