Laboratory of Biochemistry and Molecular Biology, NCI, NIH, Bethesda, MD 20892, USA.
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Nucleic Acids Res. 2021 Aug 20;49(14):8161-8176. doi: 10.1093/nar/gkab586.
The discovery of HAATIrDNA, a telomerase-negative survival mode in which canonical telomeres are replaced with ribosomal DNA (rDNA) repeats that acquire chromosome end-protection capability, raised crucial questions as to how rDNA tracts 'jump' to eroding chromosome ends. Here, we show that HAATIrDNA formation is initiated and limited by a single translocation that juxtaposes rDNA from Chromosome (Chr) III onto subtelomeric elements (STE) on Chr I or II; this rare reaction requires RNAi and the Ino80 nucleosome remodeling complex (Ino80C), thus defining an unforeseen relationship between these two machineries. The unique STE-rDNA junction created by this initial translocation is efficiently copied to the remaining STE chromosome ends, independently of RNAi or Ino80C. Intriguingly, both RNAi and Ino80C machineries contain a component that plays dual roles in HAATI subtype choice. Dcr1 of the RNAi pathway and Iec1 of Ino80C both promote HAATIrDNA formation as part of their respective canonical machineries, but both also inhibit formation of the exceedingly rare HAATISTE (where STE sequences mobilize throughout the genome and assume chromosome end protection capacity) in non-canonical, pathway-independent manners. This work provides a glimpse into a previously unrecognized crosstalk between RNAi and Ino80C in controlling unusual translocation reactions that establish telomere-free linear chromosome ends.
端粒酶阴性的 HAATIrDNA 的发现，即经典端粒被核糖体 DNA（rDNA）重复序列取代，并获得染色体末端保护能力的生存模式，提出了一个关键问题，即 rDNA 片段如何“跳跃”到侵蚀性染色体末端。在这里，我们表明，HAATIrDNA 的形成是由单个易位起始和限制的，该易位使来自染色体 III（Chr III）的 rDNA 并列到 Chr I 或 Chr II 的端粒外元件（STE）上；这种罕见的反应需要 RNAi 和 Ino80 核小体重塑复合物（Ino80C），从而定义了这两个机制之间的预期关系。这个初始易位创建的独特的 STE-rDNA 连接点被有效地复制到剩余的 STE 染色体末端，而与 RNAi 或 Ino80C 无关。有趣的是，RNAi 和 Ino80C 两种机制都包含一个在 HAATI 亚型选择中起双重作用的组件。RNAi 途径的 Dcr1 和 Ino80C 的 Iec1 都作为其各自的规范机制的一部分促进 HAATIrDNA 的形成，但它们也以非规范、非途径依赖的方式抑制极为罕见的 HAATISTE（其中 STE 序列在整个基因组中移动并获得染色体末端保护能力）的形成。这项工作提供了一个之前未被识别的 RNAi 和 Ino80C 之间的串扰的 glimpse，这种串扰控制着建立无端粒的线性染色体末端的异常易位反应。
