RNAi drives nonreciprocal translocations at eroding chromosome ends to establish telomere-free linear chromosomes.
The identification of telomerase-negative HAATI (heterochromatin amplification-mediated and telomerase-independent) cells, in which telomeres are superseded by nontelomeric heterochromatin tracts, challenged the idea that canonical telomeres are essential for chromosome linearity and raised crucial questions as to how such tracts translocate to eroding chromosome ends and confer end protection. Here we show that HAATI arises when telomere loss triggers a newly recognized illegitimate translocation pathway that requires RNAi factors. While RNAi is necessary for the translocation events that mobilize ribosomal DNA (rDNA) tracts to all chromosome ends (forming "HAATIrDNA" chromosomes), it is dispensable for HAATIrDNA maintenance. Surprisingly, Dicer (Dcr1) plays a separate, RNAi-independent role in preventing formation of the rare HAATI subtype in which a different repetitive element (the subtelomeric element) replaces telomeres. Using genetics and fusions between shelterin components and rDNA-binding proteins, we mapped the mechanism by which rDNA loci engage crucial end protection factors-despite the absence of telomere repeats-and secure end protection. Sequence analysis of HAATIrDNA genomes allowed us to propose RNA and DNA polymerase template-switching models for the mechanism of RNAi-triggered rDNA translocations. Collectively, our results reveal unforeseen roles for noncoding RNAs (ncRNAs) in assembling a telomere-free chromosome end protection device.
['Begnis|Martina|M|', 'Apte|Manasi S|MS|', 'Masuda|Hirohisa|H|', 'Jain|Devanshi|D|', 'Wheeler|David Lee|DL|', 'Cooper|Julia Promisel|JP|']
D004260:DNA Repair D004275:DNA, Ribosomal D004268:DNA-Binding Proteins D006570:Heterochromatin D034622:RNA Interference D051135:Rad51 Recombinase D043244:Ribonuclease III D012568:Schizosaccharomyces D029702:Schizosaccharomyces pombe Proteins D000089804:Shelterin Complex D016615:Telomere D034501:Telomere-Binding Proteins D020079:Terminal Repeat Sequences D014178:Translocation, Genetic
RNAi telomere ALT DNA repair cancer genome stability