TopBP1 is required at mitosis to reduce transmission of DNA damage to G1 daughter cells

Rune Troelsgaard Pedersen; Thomas Kruse; Jakob Nilsson; Vibe Hallundbæk Østergaard; Michael Lisby

doi:10.1083/jcb.201502107

TopBP1 is required at mitosis to reduce transmission of DNA damage to G1 daughter cells

Rune Troelsgaard Pedersen, Thomas Kruse, Jakob Nilsson, Vibe Hallundbæk Østergaard, Michael Lisby

Functional genomics

48 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Cell Biology
Vol/bind	210
Udgave nummer	4
Sider (fra-til)	565-582
Antal sider	18
ISSN	0021-9525
DOI	https://doi.org/10.1083/jcb.201502107
Status	Udgivet - 17 aug. 2015

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10.1083/jcb.201502107

jcb_201502107.pdfForlagets udgivne version, 3,44 MBLicens: CC BY-NC-SA

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AU - Pedersen, Rune Troelsgaard

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AU - Lisby, Michael

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N2 - 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.

AB - 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.

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TopBP1 is required at mitosis to reduce transmission of DNA damage to G1 daughter cells

Abstract

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