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

Genes Dev. 2018 Apr 1;32(7-8):537-554. doi: 10.1101/gad.311712.118. Epub 2018 Apr 13.

Abstract

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HAATI (heterochromatin amplification-mediated and telomerase-independent) cells, in which telomeres are superseded by nontelomeric heterochromatin tracts, challenged the idea that canonical telomeres are essential for chromosome linearity and raised crucial questions as to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

Keywords: ALT; DNA repair; RNAi; cancer; genome stability; telomere.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Repair
  • DNA, Ribosomal*
  • DNA-Binding Proteins / physiology
  • Heterochromatin*
  • RNA Interference*
  • Rad51 Recombinase / physiology
  • Ribonuclease III / metabolism
  • Ribonuclease III / physiology
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces / metabolism
  • Schizosaccharomyces pombe Proteins / metabolism
  • Schizosaccharomyces pombe Proteins / physiology
  • Telomere
  • Telomere-Binding Proteins / metabolism
  • Terminal Repeat Sequences
  • Translocation, Genetic*

Substances

  • DNA, Ribosomal
  • DNA-Binding Proteins
  • Heterochromatin
  • RHP51 protein, S pombe
  • Schizosaccharomyces pombe Proteins
  • Telomere-Binding Proteins
  • pot1 protein, S pombe
  • rad52 protein, S pombe
  • Rad51 Recombinase
  • Ribonuclease III