State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
University of the Chinese Academy of Sciences, Beijing, 100049, China.
Cell Death Differ. 2018 Jun;25(6):1174-1188. doi: 10.1038/s41418-017-0037-8. Epub 2018 Jan 8.
Telomeres integrity is indispensable for chromosomal stability by preventing chromosome erosion and end-to-end fusions. During meiosis, telomeres attach to the inner nuclear envelope and cluster into a highly crowded microenvironment at the bouquet stage, which requires specific mechanisms to protect the telomeres from fusion. Here, we demonstrate that germ cell-specific knockout of a shelterin complex subunit, Trf1, results in arrest of spermatocytes at two different stages. The obliterated telomere-nuclear envelope attachment in Trf1-deficient spermatocytes impairs homologue synapsis and recombination, resulting in a pachytene-like arrest, while the meiotic division arrest might stem from chromosome end-to-end fusion due to the failure of recruiting meiosis specific telomere associated proteins. Further investigations uncovered that TRF1 could directly interact with Speedy A, and Speedy A might work as a scaffold protein to further recruit Cdk2, thus protecting telomeres from fusion at this stage. Together, our results reveal a novel mechanism of TRF1, Speedy A, and Cdk2 in protecting telomere from fusion in a highly crowded microenvironment during meiosis.
端粒完整性对于染色体稳定至关重要，可防止染色体磨损和端-端融合。在减数分裂过程中，端粒附着在内核膜上，并在花束阶段聚集到一个高度拥挤的微环境中，这需要特定的机制来保护端粒免受融合。在这里，我们证明了生殖细胞特异性敲除庇护复合物亚基 Trf1 会导致精母细胞在两个不同阶段停滞。Trf1 缺陷的精母细胞中端粒-核膜附着的消失会损害同源物联会和重组，导致类似于粗线期的停滞，而减数分裂的分裂停滞可能源于染色体端-端融合，因为无法招募减数分裂特异性端粒相关蛋白。进一步的研究揭示了 TRF1 可以直接与 Speedy A 相互作用，而 Speedy A 可能作为支架蛋白进一步招募 Cdk2，从而在这个阶段保护端粒免受融合。总之，我们的结果揭示了在减数分裂过程中，TRF1、Speedy A 和 Cdk2 在高度拥挤的微环境中保护端粒免受融合的新机制。
