University of Groningen, University Medical Center Groningen, European Research Institute for the Biology of Ageing, 9713 AV, Groningen, Netherlands.
Clinic of Internal Medicine III, Oncology, Hematology, Rheumatology and Clinical Immunology, University Hospital Bonn, Bonn, Germany.
BMC Biol. 2021 Nov 20;19(1):247. doi: 10.1186/s12915-021-01167-1.
The main function of telomerase is at the telomeres but under adverse conditions telomerase can bind to internal regions causing deleterious effects as observed in cancer cells.
By mapping the global occupancy of the catalytic subunit of telomerase (Est2) in the budding yeast Saccharomyces cerevisiae, we reveal that it binds to multiple guanine-rich genomic loci, which we termed "non-telomeric binding sites" (NTBS). We characterize Est2 binding to NTBS. Contrary to telomeres, Est2 binds to NTBS in G1 and G2 phase independently of Est1 and Est3. The absence of Est1 and Est3 renders telomerase inactive at NTBS. However, upon global DNA damage, Est1 and Est3 join Est2 at NTBS and telomere addition can be observed indicating that Est2 occupancy marks NTBS regions as particular risks for genome stability.
Our results provide a novel model of telomerase regulation in the cell cycle using internal regions as "parking spots" of Est2 but marking them as hotspots for telomere addition.
端粒酶的主要功能位于端粒上，但在不利条件下，端粒酶可以结合到内部区域，从而产生有害影响，如在癌细胞中观察到的那样。
通过绘制出酿酒酵母（Saccharomyces cerevisiae）中端粒酶催化亚基（Est2）在全基因组上的占有率图谱，我们揭示出它与多个富含鸟嘌呤的基因组区域结合，我们将这些区域称为“非端粒结合位点”（NTBS）。我们对 Est2 与 NTBS 的结合进行了表征。与端粒不同的是，Est2 在 G1 和 G2 期与 Est1 和 Est3 无关，独立地与 NTBS 结合。Est1 和 Est3 的缺失使端粒酶在 NTBS 处失活。然而，当发生全基因组 DNA 损伤时，Est1 和 Est3 会与 Est2 一起结合到 NTBS 上，并且可以观察到端粒添加，这表明 Est2 的占据标志着 NTBS 区域是基因组稳定性的特别风险点。
我们的研究结果提供了一个新的细胞周期中端粒酶调控模型，该模型将内部区域作为 Est2 的“停车场”，但将它们标记为端粒添加的热点。
