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

Alberto Moreno, Jamie T. Carrington, Luca Albergante, Mohammed Al Mamun, Emma J. Haagensen, Eirini-Stavroula Komseli, Vassilis G. Gorgoulis, Timothy J. Newman, John Blow (Lead / Corresponding author)

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Abstract

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.
Original languageEnglish
Pages (from-to)E5757-E5764
Number of pages8
JournalProceedings of the National Academy of Sciences
Volume113
Issue number39
Early online date11 Aug 2016
DOIs
Publication statusPublished - 27 Sep 2016

Keywords

  • DNA replication
  • dormant origins
  • cell cycle
  • MCM
  • 53BP1
  • UFBs

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    Moreno, A., Carrington, J. T., Albergante, L., Al Mamun, M., Haagensen, E. J., Komseli, E-S., Gorgoulis, V. G., Newman, T. J., & Blow, J. (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. https://doi.org/10.1073/pnas.1603252113