TopBP1 is required at mitosis to reduce transmission of DNA damage to G1 daughter cells.
Genome integrity is critically dependent on timely DNA replication and accurate chromosome segregation. Replication stress delays replication into G2/M, which in turn impairs proper chromosome segregation and inflicts DNA damage on the daughter cells. Here we show that TopBP1 forms foci upon mitotic entry. In early mitosis, TopBP1 marks sites of and promotes unscheduled DNA synthesis. Moreover, TopBP1 is required for focus formation of the structure-selective nuclease and scaffold protein SLX4 in mitosis. Persistent TopBP1 foci transition into 53BP1 nuclear bodies (NBs) in G1 and precise temporal depletion of TopBP1 just before mitotic entry induced formation of 53BP1 NBs in the next cell cycle, showing that TopBP1 acts to reduce transmission of DNA damage to G1 daughter cells. Based on these results, we propose that TopBP1 maintains genome integrity in mitosis by controlling chromatin recruitment of SLX4 and by facilitating unscheduled DNA synthesis.
Department of Biology, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
Rune Troelsgaard
RT
Pedersen
The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
Thomas
T
Kruse
The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
Jakob
J
Nilsson
Department of Biology, University of Copenhagen, DK-2200 Copenhagen N, Denmark vibe@bio.ku.dk mlisby@bio.ku.dk.
Vibe H
VH
Oestergaard
Department of Biology, University of Copenhagen, DK-2200 Copenhagen N, Denmark vibe@bio.ku.dk mlisby@bio.ku.dk.
Michael
M
Lisby
D030161:Avian Proteins / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000502:physiology*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D016193:G1 Phase; D016195:G2 Phase; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008938:Mitosis; D009687:Nuclear Proteins / Q000502:physiology*; D021381:Protein Transport; D045522:Recombinases / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
D030161:Avian Proteins; D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D045522:Recombinases; C110513:TOPBP1 protein, human; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C542319:SLX4 protein, human