SUMO regulates the nucleolar organization upon ribosomal DNA damage to maintain genome stability

CAPELLA, MATIAS; MANDEMAKER, IMKE K; MARTÍN CABALLERO, LUCÍA; PFANDER, BORIS; JENTSCH, STEFAN; LADURNER, ANDREAS G; BRAUN, SIGURD

Simposio; Ubiquitin & Friends Symposium 2020; 2020

Vienna BioCenter

The ribosomal DNA (rDNA) locus often undergoes homologous recombination due to its repetitive nature. This results in gain or loss of individual repeats, which has been associated with neurodegenerative diseases and cancer. The nucleolar localization of rDNA is critical for its stability, as the homologous recombination machinery is excluded from the nucleolus. Therefore, damaged rDNA repeats need to be released from the nucleolus upon double-strand breaks, a conserved process from yeast to humans. However, how rDNA relocalization is controlled remains a long-standing question. Here we show that SUMO promotes the release of repeats outside the nucleolus. We discovered that SUMOylation of the nucleolar phosphatase Cdc14 impairs its association to rDNA repeats, thus triggering the phosphorylation and disruption of the complex keeping the rDNA inside the nucleolus. Upon damage, the segregase Cdc48 removes Cdc14 from the rDNA repeats through SUMO-recognition by the cofactor Ufd1. Moreover, depletion of UFD1L impairs the relocalization of damaged repeats in human cells. Interestingly, disruption of rDNA dynamics through permanent tethering is detrimental for cell survival. Our findings unveil critical steps that modulate rDNA release from the nucleolus to maintain genome stability.