title: Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells.
abstract: To prevent rereplication of genomic segments, the eukaryotic cell cycle is divided into two nonoverlapping phases. During late mitosis and G1 replication origins are "licensed" by loading MCM2-7 double hexamers and during S phase licensed replication origins activate to initiate bidirectional replication forks. Replication forks can stall irreversibly, and if two converging forks stall with no intervening licensed origin-a "double fork stall" (DFS)-replication cannot be completed by conventional means. We previously showed how the distribution of replication origins in yeasts promotes complete genome replication even in the presence of irreversible fork stalling. This analysis predicts that DFSs are rare in yeasts but highly likely in large mammalian genomes. Here we show that complementary strand synthesis in early mitosis, ultrafine anaphase bridges, and G1-specific p53-binding protein 1 (53BP1) nuclear bodies provide a mechanism for resolving unreplicated DNA at DFSs in human cells. When origin number was experimentally altered, the number of these structures closely agreed with theoretical predictions of DFSs. The 53BP1 is preferentially bound to larger replicons, where the probability of DFSs is higher. Loss of 53BP1 caused hypersensitivity to licensing inhibition when replication origins were removed. These results provide a striking convergence of experimental and theoretical evidence that unreplicated DNA can pass through mitosis for resolution in the following cell cycle.
authors: School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors: Alberto
authors: A
authors: Moreno
authors: School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors: Jamie T
authors: JT
authors: Carrington
authors: School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; School of Science and Engineering, University of Dundee, Dundee DD1 4HN, United Kingdom;
authors: Luca
authors: 0000-0001-8151-6989
authors: L
authors: Albergante
authors: School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; School of Science and Engineering, University of Dundee, Dundee DD1 4HN, United Kingdom;
authors: Mohammed
authors: M
authors: Al Mamun
authors: School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors: Emma J
authors: EJ
authors: Haagensen
authors: Department of Histology and Embryology, School of Medicine, University of Athens, GR-11527 Athens, Greece;
authors: Eirini-Stavroula
authors: ES
authors: Komseli
authors: Department of Histology and Embryology, School of Medicine, University of Athens, GR-11527 Athens, Greece; Biomedical Research Foundation of the Academy of Athens, GR-11527 Athens, Greece; Faculty Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester M20 4QL, United Kingdom.
authors: Vassilis G
authors: VG
authors: Gorgoulis
authors: School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; School of Science and Engineering, University of Dundee, Dundee DD1 4HN, United Kingdom;
authors: Timothy J
authors: TJ
authors: Newman
authors: School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom; j.j.blow@dundee.ac.uk.
authors: J Julian
authors: JJ
authors: Blow
mesh_terms: D001980:Bronchi / Q000166:cytology; D018797:Cell Cycle Proteins / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D056426:Genetic Loci; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008938:Mitosis; D009687:Nuclear Proteins / Q000378:metabolism; D034622:RNA Interference; D018741:Replication Origin; D016196:S Phase; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism
chemical_list: C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; C489423:MCM5 protein, human; D009687:Nuclear Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D004247:DNA
keywords: 53BP1; DNA replication; MCM; UFB; cell cycle