The State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai 200031, China.
School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
Nucleic Acids Res. 2020 Dec 16;48(22):12792-12803. doi: 10.1093/nar/gkaa1150.
Telomeres at the ends of eukaryotic chromosomes are essential for genome integrality and stability. In order to identify genes that sustain telomere maintenance independently of telomerase recruitment, we have exploited the phenotype of over-long telomeres in the cells that express Cdc13-Est2 fusion protein, and examined 195 strains, in which individual non-essential gene deletion causes telomere shortening. We have identified 24 genes whose deletion results in dramatic failure of Cdc13-Est2 function, including those encoding components of telomerase, Yku, KEOPS and NMD complexes, as well as quite a few whose functions are not obvious in telomerase activity regulation. We have characterized Swc4, a shared subunit of histone acetyltransferase NuA4 and chromatin remodeling SWR1 (SWR1-C) complexes, in telomere length regulation. Deletion of SWC4, but not other non-essential subunits of either NuA4 or SWR1-C, causes significant telomere shortening. Consistently, simultaneous disassembly of NuA4 and SWR1-C does not affect telomere length. Interestingly, inactivation of Swc4 in telomerase null cells accelerates both telomere shortening and senescence rates. Swc4 associates with telomeric DNA in vivo, suggesting a direct role of Swc4 at telomeres. Taken together, our work reveals a distinct role of Swc4 in telomere length regulation, separable from its canonical roles in both NuA4 and SWR1-C.
端粒位于真核生物染色体的末端，对于基因组的完整性和稳定性至关重要。为了鉴定独立于端粒酶募集而维持端粒的基因，我们利用表达 Cdc13-Est2 融合蛋白的细胞中端粒过长的表型，检查了 195 株菌株，其中单个非必需基因的缺失导致端粒缩短。我们已经鉴定出 24 个基因的缺失导致 Cdc13-Est2 功能显著失效，包括编码端粒酶、Yku、KEOPS 和 NMD 复合物组件的基因，以及相当多的其功能在端粒酶活性调节中不明显的基因。我们已经在端粒长度调节中对 Swc4（组蛋白乙酰转移酶 NuA4 和染色质重塑 SWR1（SWR1-C）复合物的共享亚基）进行了特征描述。Swc4 的缺失，而不是 NuA4 或 SWR1-C 的其他非必需亚基的缺失，导致端粒显著缩短。一致地，NuA4 和 SWR1-C 的同时解体并不影响端粒长度。有趣的是，在端粒酶缺失细胞中失活 Swc4 会加速端粒缩短和衰老速率。Swc4 在体内与端粒 DNA 结合，表明 Swc4 在端粒上具有直接作用。总之，我们的工作揭示了 Swc4 在端粒长度调节中的独特作用，与其在 NuA4 和 SWR1-C 中的典型作用分离。
