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

2015 ◽  
Vol 210 (4) ◽  
pp. 565-582 ◽  
Author(s):  
Rune Troelsgaard Pedersen ◽  
Thomas Kruse ◽  
Jakob Nilsson ◽  
Vibe H. Oestergaard ◽  
Michael Lisby
Keyword(s):  
Dna Damage ◽  
Dna Synthesis ◽  
Chromosome Segregation ◽  
Nuclear Bodies ◽  
Genome Integrity ◽  
Unscheduled Dna Synthesis ◽  
Focus Formation ◽  
Mitotic Entry ◽  
Daughter Cells ◽  
Early Mitosis

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.

scholarly journals Mus81-Eme1–dependent aberrant processing of DNA replication intermediates in mitosis impairs genome integrity

2020 ◽  
Vol 6 (50) ◽  
pp. eabc8257
Author(s):  
Nicolás Luis Calzetta ◽  
Marina Alejandra González Besteiro ◽  
Vanesa Gottifredi
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Synthesis ◽  
Chromosome Segregation ◽  
Chromosome Instability ◽  
Genome Integrity ◽  
Common Side Effect ◽  
Cancer Evolution ◽  
Mechanistic Basis ◽  
Replication Intermediates

Chromosome instability (CIN) underpins cancer evolution and is associated with drug resistance and poor prognosis. Understanding the mechanistic basis of CIN is thus a priority. The structure-specific endonuclease Mus81-Eme1 is known to prevent CIN. Intriguingly, however, here we show that the aberrant processing of late replication intermediates by Mus81-Eme1 is a source of CIN. Upon depletion of checkpoint kinase 1 (Chk1), Mus81-Eme1 cleaves under-replicated DNA engaged in mitotic DNA synthesis, leading to chromosome segregation defects. Supplementing cells with nucleosides allows the completion of mitotic DNA synthesis, restraining Mus81-Eme1–dependent DNA damage in mitosis and the ensuing CIN. We found no correlation between CIN arising from nucleotide shortage in mitosis and cell death, which were selectively linked to DNA damage load in mitosis and S phase, respectively. Our findings imply the possibility of optimizing Chk1-directed therapies by inducing cell death while curtailing CIN, a common side effect of chemotherapy.

scholarly journals DNA replication and spindle checkpoints cooperate during S phase to delay mitosis and preserve genome integrity

2014 ◽  
Vol 204 (2) ◽  
pp. 165-175 ◽  
Author(s):  
Maria M. Magiera ◽  
Elisabeth Gueydon ◽  
Etienne Schwob
Keyword(s):  
Dna Replication ◽  
Chromosome Segregation ◽  
Replication Stress ◽  
S Phase ◽  
Genome Integrity ◽  
Replication Forks ◽  
Mitotic Entry ◽  
Transient Activation ◽  
Spindle Checkpoints ◽  
Spindle Assembly Checkpoints

Deoxyribonucleic acid (DNA) replication and chromosome segregation must occur in ordered sequence to maintain genome integrity during cell proliferation. Checkpoint mechanisms delay mitosis when DNA is damaged or upon replication stress, but little is known on the coupling of S and M phases in unperturbed conditions. To address this issue, we postponed replication onset in budding yeast so that DNA synthesis is still underway when cells should enter mitosis. This delayed mitotic entry and progression by transient activation of the S phase, G2/M, and spindle assembly checkpoints. Disabling both Mec1/ATR- and Mad2-dependent controls caused lethality in cells with deferred S phase, accompanied by Rad52 foci and chromosome missegregation. Thus, in contrast to acute replication stress that triggers a sustained Mec1/ATR response, multiple pathways cooperate to restrain mitosis transiently when replication forks progress unhindered. We suggest that these surveillance mechanisms arose when both S and M phases were coincidently set into motion by a unique ancestral cyclin–Cdk1 complex.

scholarly journals PP2A-Cdc55 is responsible for mitotic arrest in DNA re-replicating cells in S. cerevisiae

2020 ◽  
Author(s):  
Shoily Khondker ◽  
Amy E. Ikui
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Arrest ◽  
Cell Cycle Checkpoints ◽  
Genome Integrity ◽  
Cyclin Dependent Kinase ◽  
Metaphase Arrest ◽  
Daughter Cells ◽  
Origin Licensing

AbstractThe cell cycle is an ordered process in which cells replicate their DNA in S-phase and divide them into two identical daughter cells in mitosis. DNA replication takes place only once per cell cycle to preserve genome integrity, which is tightly regulated by Cyclin Dependent Kinase (CDK). Formation of the pre-replicative complex, a platform for origin licensing, is inhibited through CDK-dependent phosphorylation. Failure of this control leads to re-licensing, re-replication and DNA damage. Eukaryotic cells have evolved surveillance mechanisms to maintain genome integrity, termed cell cycle checkpoints. It has been shown that the DNA damage checkpoint is activated upon the induction of DNA re-replication and arrests cell cycle in mitosis in S. cerevisiae. In this study, we show that PP2A-Cdc55 is responsible for the metaphase arrest induced by DNA re-replication, leading to dephosphorylation of APC component, Exclusion of Cdc55 from the nucleus bypassed the mitotic arrest and resulted in enhanced cell lethality in re-replicating cells. The metaphase arrest in re-replication cells was retained in the absence of Mad2, a key component of the spindle assembly checkpoint. Moreover, re-replicating cells showed the same rate of DNA damage induction in the presence or absence of Cdc55. These results indicate that PP2A-Cdc55 maintains metaphase arrest upon DNA re-replication and DNA damage through APC inhibition.

scholarly journals The Unresolved Problem of DNA Bridging

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 623 ◽  
Author(s):  
María Fernández-Casañas ◽  
Kok-Lung Chan
Keyword(s):  
Chromosome Segregation ◽  
Genome Stability ◽  
Genetic Material ◽  
Genome Integrity ◽  
Cellular Division ◽  
Daughter Cells ◽  
Dna Replication And Repair ◽  
A Cell ◽  
Chromosome Separation ◽  
Last Stage

Accurate duplication and transmission of identical genetic information into offspring cells lies at the heart of a cell division cycle. During the last stage of cellular division, namely mitosis, the fully replicated DNA molecules are condensed into X-shaped chromosomes, followed by a chromosome separation process called sister chromatid disjunction. This process allows for the equal partition of genetic material into two newly born daughter cells. However, emerging evidence has shown that faithful chromosome segregation is challenged by the presence of persistent DNA intertwining structures generated during DNA replication and repair, which manifest as so-called ultra-fine DNA bridges (UFBs) during anaphase. Undoubtedly, failure to disentangle DNA linkages poses a severe threat to mitosis and genome integrity. This review will summarize the possible causes of DNA bridges, particularly sister DNA inter-linkage structures, in an attempt to explain how they may be processed and how they influence faithful chromosome segregation and the maintenance of genome stability.

Induction of DNA damage by urethane in mouse testes: DNA binding and unscheduled DNA synthesis

1994 ◽  
Vol 24 (1) ◽  
pp. 68-74 ◽  
Author(s):  
Rene E. Sotomayor ◽  
Gary A. Sega ◽  
Fred Kadlubar
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Dna Synthesis ◽  
Unscheduled Dna Synthesis

scholarly journals Nucleus-Cytoskeleton Crosstalk During Mitotic Entry

2021 ◽  
Vol 9 ◽  
Author(s):  
Margarida Dantas ◽  
Joana T. Lima ◽  
Jorge G. Ferreira
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly ◽  
Regulatory Pathways ◽  
Mitotic Entry ◽  
Daughter Cells ◽  
Nuclear Events ◽  
Physical Forces ◽  
Biochemical Signals

In preparation for mitosis, cells undergo extensive reorganization of the cytoskeleton and nucleus, so that chromosomes can be efficiently segregated into two daughter cells. Coordination of these cytoskeletal and nuclear events occurs through biochemical regulatory pathways, orchestrated by Cyclin-CDK activity. However, recent studies provide evidence that physical forces are also involved in the early steps of spindle assembly. Here, we will review how the crosstalk of physical forces and biochemical signals coordinates nuclear and cytoplasmic events during the G2-M transition, to ensure efficient spindle assembly and faithful chromosome segregation.

scholarly journals An intrinsic S/G2 checkpoint enforced by ATR

Science ◽  
2018 ◽  
Vol 361 (6404) ◽  
pp. 806-810 ◽  
Author(s):  
Joshua C. Saldivar ◽  
Stephan Hamperl ◽  
Michael J. Bocek ◽  
Mingyu Chung ◽  
Thomas E. Bass ◽  
...  
Keyword(s):  
Dna Replication ◽  
Chromosome Segregation ◽  
Gene Network ◽  
S Phase ◽  
Genome Integrity ◽  
Control Mechanisms ◽  
Cyclin Dependent Kinase ◽  
G2 Checkpoint ◽  
A Cell ◽  
Early Mitosis

The cell cycle is strictly ordered to ensure faithful genome duplication and chromosome segregation. Control mechanisms establish this order by dictating when a cell transitions from one phase to the next. Much is known about the control of the G1/S, G2/M, and metaphase/anaphase transitions, but thus far, no control mechanism has been identified for the S/G2 transition. Here we show that cells transactivate the mitotic gene network as they exit the S phase through a CDK1 (cyclin-dependent kinase 1)–directed FOXM1 phosphorylation switch. During normal DNA replication, the checkpoint kinase ATR (ataxia-telangiectasia and Rad3-related) is activated by ETAA1 to block this switch until the S phase ends. ATR inhibition prematurely activates FOXM1, deregulating the S/G2 transition and leading to early mitosis, underreplicated DNA, and DNA damage. Thus, ATR couples DNA replication with mitosis and preserves genome integrity by enforcing an S/G2 checkpoint.

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