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Dissecting Fission Yeast Shelterin Interactions via MICro-MS Links Disruption of Shelterin Bridge to Tumorigenesis

  • Author(s): Liu, J
  • Yu, C
  • Hu, X
  • Kim, JK
  • Bierma, JC
  • Jun, HI
  • Rychnovsky, SD
  • Huang, L
  • Qiao, F
  • et al.

© 2015 The Authors. 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-functionmutants 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-centeredshelterin 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 aconnection between shelterin connectivity and tumorigenicity. Liu etal. develop a strategy that identifies contact sites within a complex without a 3D structure. Using this strategy, they dissect interactions among fission yeast shelterin components and find that failure to maintain an intact human shelterin bridge leads to tumorigenesis.

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