Abstract
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.
Highlights
DNA damage can lead to deletion, translocation and amplification of DNA in the genome, which may result in cell death, cancer and cellular senescence [1]
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
Summary
DNA damage can lead to deletion, translocation and amplification of DNA in the genome, which may result in cell death, cancer and cellular senescence [1]. The most hazardous forms of genomic damage is the DNA double-strand break (DSB) that can occur randomly in the chromosome during replication, mainly in the S phase of the cell cycle, when the replication fork is arrested by DNA damage, torsional stress, modified nucleotides, or colliding transcription complexes. The mechanism of DSB repair in repetitive sequences without rearrangement is not well understood. Insights into the cellular mechanisms that prevent these rearrangements while allowing the broken genome to be repaired will contribute to the development of novel cancer treatments and broaden our understanding of the aging process
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