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

TY - JOUR

T1 - RNAi drives nonreciprocal translocations at eroding chromosome ends to establish telomere-free linear chromosomes

AU - Begnis, Martina

AU - Apte, Manasi S.

AU - Masuda, Hirohisa

AU - Jain, Devanshi

AU - Wheeler, David Lee

AU - Cooper, Julia Promisel

N1 - Funding Information: We thank all members of the J.P.C. laboratory for useful discussion and experimental help; special thanks for advice go to our former laboratory member, Jessica Greenwood. We thank the Center for Cancer Research Sequencing Facility at National Cancer Institute Frederick for help with whole-genome sequencing. We thank Marc Buhler, Toru Nakamura, and Paul Nurse for kind gifts of reagents and advice, and Alex Kelly for discussion and comments on the manuscript. This work was supported by Cancer Research UK and the National Cancer Institute. Publisher Copyright: © 2018 Begnis et al.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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HAATI (heterochromatin amplification-mediated and telomeraseindependent) cells, in which telomeres are superseded by nontelomeric heterochromatin tracts, challenged the idea that canonical telomeres are essential for chromosome linearity and raised crucial questions as to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.

AB - 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.

KW - ALT

KW - Cancer

KW - DNA repair

KW - Genome stability

KW - RNAi

KW - Telomere

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U2 - 10.1101/gad.311712.118

DO - 10.1101/gad.311712.118

M3 - Article

C2 - 29654060

SN - 0890-9369

VL - 32

SP - 537

EP - 554

JO - Genes and Development

JF - Genes and Development

IS - 7-8

ER -