title: The splicing factor U2AF65 stabilizes TRF1 protein by inhibiting its ubiquitin-dependent proteolysis.
abstract: The human telomeric protein TRF1 is a component of the six-subunit protein complex shelterin, which provides telomere protection by organizing the telomere into a high-order structure. TRF1 functions as a negative regulator of telomere length by controlling the access of telomerase to telomeres. Thus, the cellular abundance of TRF1 at telomeres should be maintained and tightly regulated to ensure proper telomere function. Here, we identify U2 small nuclear ribonucleoprotein (snRNP) auxiliary factor 65 (U2AF65), an essentialpre-mRNA splicingfactor, as a novel TRF1-interacting protein. U2AF65 interacts with TRF1 in vitro and in vivo and is capable of stabilizing TRF1 protein by inhibiting its ubiquitin-dependent proteolysis. We also found that U2AF65 interferes with the interaction between TRF1 and Fbx4, an E3 ubiquitin ligase for TRF1. Depletion of endogenous U2AF65 expression by short interfering RNA (siRNA) reduced the stability of endogenous TRF1 whereas overexpression of U2AF65 significantly extended the half-life of TRF1. These findings demonstrate that U2AF65 plays a critical role in regulating the level of TRF1 through physical interaction and ubiquitin-mediated proteolysis. Hence, U2AF65 represents a new route for modulating TRF1 function at telomeres.
authors.affiliation: Departments of Systems Biology and Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Jeonghee
authors.initials: J
authors.lastname: Kim
authors.affiliation: Departments of Systems Biology and Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749, Republic of Korea. Electronic address: topoviro@yonsei.ac.kr.
authors.forename: In Kwon
authors.initials: IK
authors.lastname: Chung
mesh_terms: D044783:F-Box Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D012261:Ribonucleoproteins / Q000737:chemistry / Q000378:metabolism*; D000072668:Splicing Factor U2AF; D035321:Telomeric Repeat Binding Protein 1 / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D044783:F-Box Proteins; C508146:FBXO4 protein, human; D009687:Nuclear Proteins; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; D035321:Telomeric Repeat Binding Protein 1; C000607494:U2AF2 protein, human; D014452:Ubiquitins
keywords: Fbx4; TRF1; Telomere; U2AF65; Ubiquitination