Projects per year
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.
|Number of pages||8|
|Journal||Proceedings of the National Academy of Sciences|
|Early online date||11 Aug 2016|
|Publication status||Published - 27 Sept 2016|
- DNA replication
- dormant origins
- cell cycle
FingerprintDive into the research topics of 'Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells'. Together they form a unique fingerprint.
- 2 Finished
Dynamics of Fundamental Cellular Processes by Live Cell and Tissue Imaging
MacDonald, M., McGloin, D., McKenna, S., Storey, K., Swedlow, J. & Weijer, K.
1/01/13 → 31/12/17
Understanding the Cellular Response to Replication Inhibition (Senior Investigator Award)
1/09/12 → 31/08/21