UC Berkeley

The survival and fitness of an organism rely on faithful transmission of the genome. In sexually reproducing organisms, genome transmission requires a specialized cell division named meiosis, in which the parental genome is shuffled and halved. The kinetochore, a conserved protein complex that mediates chromosome segregation, is a key player in meiosis. Here we investigated how the budding yeast kinetochore undergoes dynamic changes in this specialized cell division. The microtubule-binding part of the kinetochore (outer kinetochore) dissociates from the chromosomes in meiotic prophase and reassembles before the meiotic divisions. This dynamic behavior is crucial to establish the meiosis-specific chromosome segregation. We have discovered a multi-level network that regulates the dynamic kinetochore behavior by controlling the abundance of one single kinetochore subunit, Ndc80. Ndc80 is downregulated in meiotic prophase and later re-synthesized during the meiotic divisions. This fluctuation in the Ndc80 level requires regulation on Ndc80 synthesis and turnover. Central to the Ndc80 synthesis regulation is the toggling of two NDC80 mRNAs: (1) a coding mRNA that is translated into Ndc80 protein, and (2) a 5’-extended mRNA termed LUTI. Rather than coding for Ndc80, LUTI expression impedes the expression of the coding mRNA via chromatin modifications, leading to Ndc80 synthesis repression. Two meiotic master transcription factors, Ime1 and Ndt80, regulate the expression of LUTI and the coding mRNA, respectively, and integrate Ndc80 regulation into the larger meiotic program. Besides synthesis, Ndc80 degradation is temporally controlled: Ndc80 is degraded in meiotic prophase and not in metaphase I. Ndc80 degradation requires active proteasomes, a degron sequence at Ndc80’s N-terminus, and Aurora B phosphorylation on Ndc80, which is known to correct erroneous microtubule-kinetochore attachments and is rewired to degrade Ndc80 in meiotic prophase. Crucially, mis-regulation of Ndc80 abundance disrupts chromosome segregation, gamete formation, and progeny fitness, highlighting the importance of Ndc80 modulation. Altogether, this work reveals a beautiful case in evolution in which the gene expression, turnover, and activity of the kinetochore are tuned to accommodate the specialized chromosome segregation program meiosis.