Breaks in the 45S rDNA Lead to Recombination-Mediated Loss of Repeats

• Human cells are highly sensitive to breaks in 45S, but not 5S, rDNA repeats
• Homologous recombination inhibits break repair in 45S rDNA
• SMC5 contributes to recombination-mediated repair of rDNA breaks
• Recombination-driven repair of 45S rDNA results in loss of repeats and viability

SummaryrDNA repeats constitute the most heavily transcribed region in the human genome. Tumors frequently display elevated levels of recombination in rDNA, indicating that the repeats are a liability to the genomic integrity of a cell. However, little is known about how cells deal with DNA double-stranded breaks in rDNA. Using selective endonucleases, we show that human cells are highly sensitive to breaks in 45S but not the 5S rDNA repeats. We find that homologous recombination inhibits repair of breaks in 45S rDNA, and this results in repeat loss. We identify the structural maintenance of chromosomes protein 5 (SMC5) as contributing to recombination-mediated repair of rDNA breaks. Together, our data demonstrate that SMC5-mediated recombination can lead to error-prone repair of 45S rDNA repeats, resulting in their loss and thereby reducing cellular viability.

Graphical AbstractFigure optionsDownload as PowerPoint slide