RNAi drives nonreciprocal translocations at eroding chromosome ends to establish telomere-free linear chromosomes

Martina Begnis, Manasi S. Apte, Hirohisa Masuda, Devanshi Jain, David Lee Wheeler, Julia Promisel Cooper

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The identification of telomerase-negative HAATI (heterochromatin amplification-mediated and telomeraseindependent) cells, in which telomeres are superseded by nontelomeric heterochromatin tracts, challenged the idea that canonical telomeres are essential for chromosome linearity and raised crucial questions as to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.

Original languageEnglish (US)
Pages (from-to)537-554
Number of pages18
JournalGenes and Development
Volume32
Issue number7-8
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Keywords

  • ALT
  • Cancer
  • DNA repair
  • Genome stability
  • RNAi
  • Telomere

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