Journal
NUCLEIC ACIDS RESEARCH
Volume 49, Issue 12, Pages 6817-6831Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab502
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Funding
- Agence Nationale de la Recherche [ANR-14-CE10-021 DI-CENS, ANR-15-CE12-0007 DNA-Life]
- Fondation ARC pour la Recherche sur le Cancer
- Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA)
- Electricitede France
- CEA
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Chromosome fusions play a critical role in genome stability, particularly in cells with telomere dysfunctions or exposed to DNA breakage. Genetic analysis in budding yeast can quantify the basal rate of chromosome fusions, showing that factors at telomeres influence fusion occurrence. The study also provides evidence of chromosomal rearrangements induced by ionizing radiation.
Chromosome fusions threaten genome integrity and promote cancer by engaging catastrophic mutational processes, namely chromosome breakage-fusion-bridge cycles and chromothripsis. Chromosome fusions are frequent in cells incurring telomere dysfunctions or those exposed to DNA breakage. Their occurrence and therefore their contribution to genome instability in unchallenged cells is unknown. To address this issue, we constructed a genetic assay able to capture and quantify rare chromosome fusions in budding yeast. This chromosome fusion capture (CFC) assay relies on the controlled inactivation of one centromere to rescue unstable dicentric chromosome fusions. It is sensitive enough to quantify the basal rate of end-to-end chromosome fusions occurring in wild-type cells. These fusions depend on canonical nonhomologous end joining (NHEJ). Our results show that chromosome end protection results from a trade-off at telomeres between positive effectors (Rif2, Sir4, telomerase) and a negative effector partially antagonizing them (Rift). The CFC assay also captures NHEJ-dependent chromosome fusions induced by ionizing radiation. It provides evidence for chromosomal rearrangements stemming from a single photon-matter interaction.
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