期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 39, 页码 E5757-E5764出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1603252113
关键词
DNA replication; MCM; cell cycle; 53BP1; UFB
资金
- Wellcome Trust [WT096598MA, 097945/B/11/Z]
- Greek General Secretariat for Research and Technology Program of Excellence II (Aristeia II) Grant [3020]
- Dundee Imaging Facility
- Wellcome Trust Award [097945/B/11/Z]
- Medical Research Council Award [MR/K015869/1]
- Flow Cytometry and Cell Sorting Facility at the University of Dundee
- Experimental Research Center Elpen Scholarship
- National Scholarships Foundation-Siemens Aristeia Fellowship
- Medical Research Council [MR/K015869/1] Funding Source: researchfish
- BBSRC [BBS/E/D/20310000] Funding Source: UKRI
- MRC [MR/K015869/1] Funding Source: UKRI
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.
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