Defining the mechanisms and consequences of noncanonical telomere functions

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Abstract The canonical functions attributed to telomeres in textbooks are to protect chromosome ends from degradation and fusion, both of which are confirmed drivers of genome instability and tumorigenesis. We have discovered two new and unforeseen roles for telomeres that are crucial for safeguarding the genome. First, we found that by interacting during meiotic prophase with the LINC complex (linker of nucleo- and cyto-skeleton), which spans the nuclear envelope, telomeres promote the nuclear envelope breakdown needed for spindle formation and the meiotic nuclear divisions. Remarkably, centromeres perform this function analogously in mitotic cell cycles, and indeed sporadic contacts between centromeres and LINC during meiotic prophase can rescue the loss of telomere-LINC contacts, indicating a surprising instance of telomere-centromere interchangeability. What features of telomeres and centromeres endow them with the capacity to control nuclear envelope breakdown and therefore cell cycle progression? Here we propose a series of experiments to answer this question. Second, we found that by providing a nuclear microdomain conducive to centromere assembly, telomeres rescue a surprising tendency of centromeres to become dismantled upon meiotic onset by the very factors (the meiotic endonuclease Spo11 and the meiosis-specific cohesin Rec8) that define meiosis. Indeed, we found that expression of Spo11 or Rec8 (which are normally meiosis-specific) in proliferating cells induces centromere dismantlement and chromosome missegregation. Here we propose to determine the mechanisms of Spo11- and Rec8-mediated centromere dismantlement, how telomeres promote the reassembly of dismantled centromeres, and whether these observations are relevant to the growing list of human cancers that mis-express meiotic proteins. These studies will open up new frontiers by defining at the molecular level unanticipated features of two key lynchpins of chromosome stability, telomeres and centromeres.