title: 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress.
abstract: Completion of genome duplication is challenged by structural and topological barriers that impede progression of replication forks. Although this can seriously undermine genome integrity, the fate of DNA with unresolved replication intermediates is not known. Here, we show that mild replication stress increases the frequency of chromosomal lesions that are transmitted to daughter cells. Throughout G1, these lesions are sequestered in nuclear compartments marked by p53-binding protein 1 (53BP1) and other chromatin-associated genome caretakers. We show that the number of such 53BP1 nuclear bodies increases after genetic ablation of BLM, a DNA helicase associated with dissolution of entangled DNA. Conversely, 53BP1 nuclear bodies are partially suppressed by knocking down SMC2, a condensin subunit required for mechanical stability of mitotic chromosomes. Finally, we provide evidence that 53BP1 nuclear bodies shield chromosomal fragile sites sequestered in these compartments against erosion. Together, these data indicate that restoration of DNA or chromatin integrity at loci prone to replication problems requires mitotic transmission to the next cell generations.
authors.affiliation: Centre for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lukas
authors.forename: Velibor
authors.initials: V
authors.lastname: Savic
authors.forename: Simon
authors.initials: S
authors.lastname: Bekker-Jensen
authors.forename: Carsten
authors.initials: C
authors.lastname: Doil
authors.forename: Beate
authors.initials: B
authors.lastname: Neumann
authors.forename: Ronni Sølvhøj
authors.initials: RS
authors.lastname: Pedersen
authors.forename: Merete
authors.initials: M
authors.lastname: Grøfte
authors.forename: Kok Lung
authors.initials: KL
authors.lastname: Chan
authors.forename: Ian David
authors.initials: ID
authors.lastname: Hickson
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D002875:Chromosomes / Q000648:ultrastructure*; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism; D004261:DNA Replication; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008938:Mitosis; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D002843:Chromatin; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D004247:DNA; D004265:DNA Helicases