Polymerization Defects within Human Telomerase Are Distinct from Telomerase RNA and TEP1 Binding

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Abstract
During the meiotic cell cycle, a surveillance mechanism called the “pachytene checkpoint” ensures proper chromosome segregation by preventing meiotic progression when recombination and chromosome synapsis are defective. The silencing protein Dot1 (also known as Pch1) is required for checkpoint-mediated pachytene arrest of thezip1 and dmc1 mutants ofSaccharomyces cerevisiae. In the absence ofDOT1, the zip1 and dmc1mutants inappropriately progress through meiosis, generating inviable meiotic products. Other components of the pachytene checkpoint include the nucleolar protein Pch2 and the heterochromatin component Sir2. Indot1, disruption of the checkpoint correlates with the loss of concentration of Pch2 and Sir2 in the nucleolus. In addition to its checkpoint function, Dot1 blocks the repair of meiotic double-strand breaks by a Rad54-dependent pathway of recombination between sister chromatids. In vegetative cells, mutation ofDOT1 results in delocalization of Sir3 from telomeres, accounting for the impaired telomeric silencing in dot1.