Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells

Moreno, Alberto, Carrington, Jamie T., Albergante, Luca, Al Mamun, Mohammed, Haagensen, Emma J., Komseli, Eirini-Stavroula, Gorgoulis, Vassilis G., Newman, Timothy J. and Blow, J. Julian (2016) Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells. Proceedings of the National Academy of Sciences, 113 (39). E5757-E5764. ISSN 1091-6490

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To prevent re-replication of genomic segments, the eukaryotic cell cycle is divided into two non-overlapping 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 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 agrees with theoretical predictions of DFSs. 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 are 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.

Item Type: Article
Additional Information: This work was supported by Wellcome Trust Grants WT096598MA and 097945/B/11/Z; Greek General Secretariat for Research and Technology Program of Excellence II (Aristeia II) Grant 3020 (to V.G.G.); the Dundee Imaging Facility, supported by Wellcome Trust Award 097945/B/11/Z and Medical Research Council Award MR/K015869/1; and the Flow Cytometry and Cell Sorting Facility at the University of Dundee. V.G.G. and E.-S.K. received an Experimental Research Center Elpen Scholarship and National Scholarships Foundation-Siemens Aristeia Fellowship.
Uncontrolled Keywords: dna replication,dormant origins,cell cycle,mcm,53bp1,ufbs
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Depositing User: LivePure Connector
Date Deposited: 10 Jun 2024 15:30
Last Modified: 10 Jun 2024 15:31
URI: https://ueaeprints.uea.ac.uk/id/eprint/95467
DOI: 10.1073/pnas.1603252113

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