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

Lookup NU author(s): Dr Emma Haagensen

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).

Abstract

To prevent re-replication of genomic segments, the eukaryotic cell cycle isdivided into two non-overlapping phases. During late mitosis and G1 replicationorigins are ‘licensed’ by loading MCM2-7 double hexamers and during S phaselicensed replication origins activate to initiate bidirectional replication forks.Replication forks can stall irreversibly, and if two converging forks stall with nointervening licensed origin - a ‘double fork stall’ (DFS) - replication cannot becompleted by conventional means. We previously showed how the distribution ofreplication origins in yeasts promotes complete genome replication even in thepresence of irreversible fork stalling. This analysis predicts that DFSs are rare inyeasts but highly likely in large mammalian genomes. Here we show thatcomplementary strand synthesis in early mitosis, ultrafine anaphase bridges andG1-specific 53BP1 nuclear bodies provide a mechanism for resolving unreplicatedDNA at DFSs in human cells. When origin number was experimentally altered, thenumber of these structures closely agrees with theoretical predictions of DFSs.53BP1 is preferentially bound to larger replicons, where the probability of DFSs ishigher. Loss of 53BP1 caused hypersensitivity to licensing inhibition whenreplication origins are removed. These results provide a striking convergence ofexperimental and theoretical evidence that unreplicated DNA can pass throughmitosis for resolution in the following cell cycle.

Publication metadata

Author(s): Moreno A, Carrington JT, Albergante L, AlMamuna M, Haagensen EJ, Komselic ES, Gourgolis VG, Newman TJ, Blow JJ

Publication type: Article

Publication status: Published

Journal: PNAS

Year: 2016

Volume: 113

Issue: 39

Pages: E5757-E5764

Print publication date: 27/09/2016

Online publication date: 11/08/2016

Acceptance date: 06/07/2016

Date deposited: 24/08/2016

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences

URL: http://dx.doi.org/10.1073/pnas.1603252113

DOI: 10.1073/pnas.1603252113

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