Ubiquitin Ligase RLIM Modulates Telomere Length Homeostasis through a Proteolysis of TRF1.
The telomeric protein TRF1 negatively regulates telomere length by inhibiting telomerase access at the telomere termini, suggesting that the protein level of TRF1 at telomeres is tightly regulated. Regulation of TRF1 protein abundance is essential for proper telomere function and occurs primarily through post-translational modifications of TRF1. Here we describe RLIM, a RING H2 zinc finger protein with intrinsic ubiquitin ligase activity, as a TRF1-interacting protein. RLIM increases TRF1 turnover by targeting it for degradation by the proteasome in a ubiquitin-dependent manner, independently of Fbx4, which is known to interact with and negatively regulate TRF1. Whereas overexpression of RLIM decreases the level of TRF1 protein, depletion of endogenous RLIM expression by small hairpin RNA increases the level of TRF1 and leads to telomere shortening, thereby impairing cell growth. These results demonstrate that RLIM is involved in the negative regulation of TRF1 function through physical interaction and ubiquitin-mediated proteolysis. Hence, RLIM represents a new pathway for telomere maintenance by modulating the level of TRF1 at telomeres.
Her
Yoon Ra
YR
Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Chung
In Kwon
IK
D002460:Cell Line; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D044783:F-Box Proteins; C508146:FBXO4 protein, human; D012097:Repressor Proteins; D035321:Telomeric Repeat Binding Protein 1; D025801:Ubiquitin; C492370:RLIM protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex