Dissecting Fission Yeast Shelterin Interactions via MICro-MS Links Disruption of Shelterin Bridge to Tumorigenesis
Copyright policy )Dissecting Fission Yeast Shelterin Interactions via MICro-MS Links Disruption of Shelterin Bridge to Tumorigenesis
Shelterin, a six-member complex, protects telomeres from nucleolytic attack and regulates their elongation by telomerase. Here, we have developed a strategy, called MICro-MS (Mapping Interfaces via Crosslinking-Mass Spectrometry), that combines crosslinking-mass spectrometry and phylogenetic analysis to identify contact sites within the complex. This strategy allowed identification of separation-of-function mutants of fission yeast Ccq1, Poz1, and Pot1 that selectively disrupt their respective interactions with Tpz1. The various telomere dysregulation phenotypes observed in these mutants further emphasize the critical regulatory roles of Tpz1-centered shelterin interactions in telomere homeostasis. Furthermore, the conservation between fission yeast Tpz1-Pot1 and human TPP1-POT1 interactions led us to map a human melanoma-associated POT1 mutation (A532P) to the TPP1-POT1 interface. Diminished TPP1-POT1 interaction caused by hPOT1-A532P may enable unregulated telomere extension, which, in turn, helps cancer cells to achieve replicative immortality. Therefore, our study reveals a connection between shelterin connectivity and tumorigenicity.
- University of California United States
- UNIVERSITY OF CALIFORNIA-IRVINE
- UNIVERSITY OF CALIFORNIA-IRVINE
- University of California United States
- University of California, Berkely United States
Models, Molecular, 570, Skin Neoplasms, QH301-705.5, Carcinogenesis, Telomere-Binding Proteins, Medical Physiology, 610, Sequence Homology, Aminopeptidases, Article, Mass Spectrometry, Shelterin Complex, Models, Gene Expression Regulation, Fungal, Schizosaccharomyces, Genetics, 2.1 Biological and endogenous factors, Humans, Protein Interaction Domains and Motifs, Biology (General), Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Telomerase, Melanoma, Cancer, Binding Sites, Sequence Homology, Amino Acid, Molecular, Telomere Homeostasis, Biological Sciences, Telomere, DNA-Binding Proteins, Amino Acid, Biological sciences, Fungal, Gene Expression Regulation, Mutation, Biochemistry and Cell Biology, Schizosaccharomyces pombe Proteins, Protein Multimerization, Serine Proteases, Carrier Proteins, Signal Transduction, Protein Binding
Models, Molecular, 570, Skin Neoplasms, QH301-705.5, Carcinogenesis, Telomere-Binding Proteins, Medical Physiology, 610, Sequence Homology, Aminopeptidases, Article, Mass Spectrometry, Shelterin Complex, Models, Gene Expression Regulation, Fungal, Schizosaccharomyces, Genetics, 2.1 Biological and endogenous factors, Humans, Protein Interaction Domains and Motifs, Biology (General), Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Telomerase, Melanoma, Cancer, Binding Sites, Sequence Homology, Amino Acid, Molecular, Telomere Homeostasis, Biological Sciences, Telomere, DNA-Binding Proteins, Amino Acid, Biological sciences, Fungal, Gene Expression Regulation, Mutation, Biochemistry and Cell Biology, Schizosaccharomyces pombe Proteins, Protein Multimerization, Serine Proteases, Carrier Proteins, Signal Transduction, Protein Binding
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