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Nuclear envelope attachment of telomeres limits TERRA and telomeric rearrangements in quiescent fission yeast cells.

ABSTRACT: Telomere anchoring to nuclear envelope (NE) is a key feature of nuclear genome architecture. Peripheral localization of telomeres is important for chromatin silencing, telomere replication and for the control of inappropriate recombination. Here, we report that fission yeast quiescent cells harbor predominantly a single telomeric cluster anchored to the NE. Telomere cluster association to the NE relies on Rap1-Bqt4 interaction, which is impacted by the length of telomeric sequences. In quiescent cells, reducing telomere length or deleting bqt4, both result in an increase in transcription of the telomeric repeat-containing RNA (TERRA). In the absence of Bqt4, telomere shortening leads to deep increase in TERRA level and the concomitant formation of subtelomeric rearrangements (STEEx) that accumulate massively in quiescent cells. Taken together, our data demonstrate that Rap1-Bqt4-dependent telomere association to NE preserves telomere integrity in post-mitotic cells, preventing telomeric transcription and recombination. This defines the nuclear periphery as an area where recombination is restricted, creating a safe zone for telomeres of post-mitotic cells.

SUBMITTER: Maestroni L

PROVIDER: S-EPMC7102995 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Eroded telomeres are rearranged in quiescent fission yeast cells through duplications of subtelomeric sequences.

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Protection of telomeres by the Ku protein in fission yeast.

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Project description:Interstitial telomeric sequences (ITSs) are present in many eukaryotic genomes and are linked to genome instabilities and disease in humans. The mechanisms responsible for ITS-mediated genome instability are not understood in molecular detail. Here, we use a model Saccharomyces cerevisiae system to characterize genome instability mediated by yeast telomeric (Ytel) repeats embedded within an intron of a reporter gene inside a yeast chromosome. We observed a very high rate of small insertions and deletions within the repeats. We also found frequent gross chromosome rearrangements, including deletions, duplications, inversions, translocations, and formation of acentric minichromosomes. The inversions are a unique class of chromosome rearrangement involving an interaction between the ITS and the true telomere of the chromosome. Because we previously found that Ytel repeats cause strong replication fork stalling, we suggest that formation of double-stranded DNA breaks within the Ytel sequences might be responsible for these gross chromosome rearrangements.

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Sequence-specific binding of Taz1p dimers to fission yeast telomeric DNA.

Project description:The fission yeast (Schizosaccharomyces pombe) taz1 gene encodes a telomere-associated protein. It contains a single copy of a Myb-like motif termed the telobox that is also found in the human telomere binding proteins TRF1 and TRF2, and Tbf1p, a protein that binds to sequences found within the sub-telomeric regions of budding yeast (Saccharomyces cerevisiae) chromosomes. Taz1p was synthesised in vitro and shown to bind to a fission yeast telomeric DNA fragment in a sequence specific manner that required the telobox motif. Like the mammalian TRF proteins, Taz1p bound to DNA as a preformed homodimer. The isolated Myb-like domain was also capable of sequence specific DNA binding, although with less specificity than the full-length dimer. Surprisingly, a protein extract produced from a taz1- fission yeast strain still contained the major telomere binding activity (complex I) we have characterised previously, suggesting that there could be other abundant telomere binding proteins in fission yeast. One candidate, SpX, was also synthesised in vitro, but despite the presence of two telobox domains, no sequence specific binding to telomeric DNA was detected.

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The fission yeast MRN complex tethers dysfunctional telomeres for NHEJ repair.

Project description:Telomeres protect the natural ends of chromosomes from being repaired as deleterious DNA breaks. In fission yeast, absence of Taz1 (homologue of human TRF1 and TRF2) renders telomeres vulnerable to DNA repair. During the G1 phase, when non-homologous end joining (NHEJ) is upregulated, taz1Δ cells undergo telomere fusions with consequent loss of viability. Here, we show that disruption of the fission yeast MRN (Rad23(MRE11)-Rad50-Nbs1) complex prevents NHEJ at telomeres and, as a result, rescues taz1Δ lethality in G1. Neither Tel1(ATM) activation nor 5'-end resection was required for telomere fusion. Nuclease activity of Rad32(MRE11) was also dispensable for NHEJ. Mutants unable to coordinate metal ions required for nuclease activity were proficient in NHEJ repair. In contrast, Rad32(MRE11) mutations that affect binding and/or positioning of DNA ends leaving the nuclease function largely unaffected also impaired NHEJ at telomeres and restored the viability of taz1Δ in G1. Consistently, MRN structural integrity but not nuclease function is also required for NHEJ of independent DNA ends in a novel split-molecule plasmid assay. Thus, MRN acts to tether unlinked DNA ends, allowing for efficient NHEJ.

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