title: Breaks in the 45S rDNA Lead to Recombination-Mediated Loss of Repeats.
abstract: rDNA 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.
authors.affiliation: Division of Cell Biology I, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: d.o.warmerdam@umcg.nl.
authors.forename: Daniël O
authors.initials: DO
authors.lastname: Warmerdam
authors.affiliation: Division of Cell Biology I, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van den Berg
authors.affiliation: Division of Cell Biology I, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: r.medema@nki.nl.
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004720:Endonucleases / Q000378:metabolism; D015894:Genome, Human; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D010766:Phosphorylation; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism*; D012341:RNA, Ribosomal, 5S / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D060888:Real-Time Polymerase Chain Reaction; D059008:Time-Lapse Imaging
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D012335:RNA, Ribosomal; D012341:RNA, Ribosomal, 5S; C088179:RNA, ribosomal, 45S; C432931:SMC5 protein, human; D004720:Endonucleases