Journal
PLOS GENETICS
Volume 15, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1008103
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Funding
- JSPS KAKENHI [JP16K20987, JP18K06056, JP17H01443]
- Takeda Science Foundation
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The ribosomal RNA genes (rDNA) comprise a highly repetitive gene cluster. The copy number of genes at this locus can readily change and is therefore one of the most unstable regions of the genome. DNA damage in rDNA occurs after binding of the replication fork blocking protein Fob1 in S phase, which triggers unequal sister chromatid recombination. However, the precise mechanisms by which such DNA double-strand breaks (DSBs) are repaired is not well understood. Here, we demonstrate that the conserved protein kinase Tel1 maintains rDNA stability after replication fork arrest. We show that rDNA associates with nuclear pores, which is dependent on DNA damage checkpoint kinases Mec1/Tel1 and replisome component Tof1. These findings suggest that rDNA-nuclear pore association is due to a replication fork block and subsequent DSB. Indeed, quantitative microscopy revealed that rDNA is relocated to the nuclear periphery upon induction of a DSB. Finally, rDNA stability was reduced in strains where this association with the nuclear envelope was prevented, which suggests its importance for avoiding improper recombination repair that could induce repeat instability. Author summary Ribosomal RNA genes (rDNA) comprise an unstable region of the genome due to their highly repetitive structure and elevated levels of transcription. Collision between transcription and replication machineries of rDNA, which may lead to DNA damage in the form of a double-stranded break, is avoided by the replication fork barrier. When such a break is repaired by homologous recombination with a repeat on the sister chromatid, the abundance of homologous sequences may lead to a change in copy number. In most organisms, however, only small variations in copy number are observed, indicating that the rDNA is stably maintained. Our results suggest that some parts of rDNA become localized to the nuclear pore complex in a DNA double-strand break-dependent manner. This localization requires the protein kinase Tel1, which is involved in the DNA damage response pathway, and factors that recruit condensin, which facilitates condensation and segregation of rDNA during mitosis. We found that the rDNA becomes unstable when association with the nuclear envelope was prevented. Thus, the localization represents a unique strategy for maintaining repeat integrity after DNA damage.
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