Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements

Deng, Liyuan; Wu, Ryan; Sonneville, Rémi; Kochenova, Olga V.; Labib, Karim; Pellman, David; Walter, Johannes C.

doi:10.1016/j.molcel.2018.12.021

Cited by 126 publications

(170 citation statements)

References 79 publications

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“…Although there is a low frequency of complex rearrangement initially associated with chromosome bridges in the first interphase after the bridge has formed, we hypothesized that additional DNA damage might arise downstream of bridge breakage. First, chromosome bridges contain segments of incomplete DNA replication and probably stalled replication forks that could undergo replication fork breakage upon entry into mitosis (51, 52). Second, we found that complex rearrangements were frequent in the second generation (i.e.…”

Section: Resultsmentioning

confidence: 99%

“…When this occurs, under-replicated bridge or micronuclear DNA will suddenly gain access to the pool of replication factors that had been sequestered in the primary nucleus throughout interphase. Access to replication factors, coupled with high mitotic cyclin-dependent kinase activity (51, 73), likely then activates replication on this incompletely replicated DNA. The DNA damage resulting from mitotic DNA replication may have a number of causes including the well-described activation of structure-specific endonucleases in mitosis (74) and/or the recently discovered cleavage of stalled DNA replication forks that occurs because of removal of the MCM2-7 replicative helicase from mitotic chromosomes (51, 75).…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms Generating Cancer Genome Complexity From A Single Cell Division Error

Umbreit

Chen

Lynch

et al. 2019

Preprint

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154

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ABSTRACTThe chromosome breakage-fusion-bridge (BFB) cycle is a mutational process that produces gene amplification and genome instability. Signatures of BFB cycles can be observed in cancer genomes with chromothripsis, another catastrophic mutational process. Here, we explain this association by identifying a mutational cascade downstream of chromosome bridge formation that generates increasing amounts of chromothripsis. We uncover a new role for actomyosin forces in bridge breakage and mutagenesis. Chromothripsis then accumulates starting with aberrant interphase replication of bridge DNA, followed by an unexpected burst of mitotic DNA replication, generating extensive DNA damage. Bridge formation also disrupts the centromeric epigenetic mark, leading to micronucleus formation that itself promotes chromothripsis. We show that this mutational cascade generates the continuing evolution and sub-clonal heterogeneity characteristic of many human cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mechanisms Generating Cancer Genome Complexity From A Single Cell Division Error

Umbreit

Chen

Lynch

et al. 2019

Preprint

Self Cite

154

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“…These terminally arrested forks and their associated replisomes persist until mitosis and one possibility is that their presence might protect the parental DNA at stalled forks from premature nucleolytic attack. Mitotic replisome disassembly is driven by the polyubiquitination of the CMG component MCM7 by the E3-ubiquitin ligase TRAIP (TRAF-interacting protein) [ 71 , 72 , 73 ]. TRAIP-directed replisome disassembly is an early requirement for MiDAS.…”

Section: Mitotic Dna Repairmentioning

confidence: 99%

Under-Replicated DNA: The Byproduct of Large Genomes?

Bertolin

Hoffmann

Gottifredi

2020

Cancers

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In this review, we provide an overview of how proliferating eukaryotic cells overcome one of the main threats to genome stability: incomplete genomic DNA replication during S phase. We discuss why it is currently accepted that double fork stalling (DFS) events are unavoidable events in higher eukaryotes with large genomes and which responses have evolved to cope with its main consequence: the presence of under-replicated DNA (UR-DNA) outside S phase. Particular emphasis is placed on the processes that constrain the detrimental effects of UR-DNA. We discuss how mitotic DNA synthesis (MiDAS), mitotic end joining events and 53BP1 nuclear bodies (53BP1-NBs) deal with such specific S phase DNA replication remnants during the subsequent phases of the cell cycle.

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“…Activation to promote CMG unloading at stalled replication forks [56] G2/M checkpoint maintenance [57] FA core complex chromatin localization in G2/M [58,59] Interaction with TopBP1 [60] Regulation of DNA repair pathway [61] DSB repair by synthesis-dependent strand annealing [62] Inhibition of FOXO1 induced-apoptosis in presence of DNA damage [63] Regulation of DNA resection and repair pathway choice [64] Mitotic entry…”

Section: Bp1 Rnf8mentioning

confidence: 99%

“…Thus, TRAIP drives replisome disassembly at those under-replicated CFS loci, thereby allowing access to replication fork for the specific factors in charge for mitotic DNA synthesis [194]. In addition, the activity of TRAIP during mitosis seems to be regulated by Cdk1-Cyclin B1 complexes [56,194,195], which control the accurate timing of mitosis and also regulate the switch from conventional DNA replication to MiDAS machineries (Table 1). Together, these data suggest that the mechanisms of MiDAS have only just started to be unraveled.…”

Section: Mitotic Dna Synthesismentioning

confidence: 99%

Working on Genomic Stability: From the S-Phase to Mitosis

Ovejero

Bueno

Sacristán

2020

Genes

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Fidelity in chromosome duplication and segregation is indispensable for maintaining genomic stability and the perpetuation of life. Challenges to genome integrity jeopardize cell survival and are at the root of different types of pathologies, such as cancer. The following three main sources of genomic instability exist: DNA damage, replicative stress, and chromosome segregation defects. In response to these challenges, eukaryotic cells have evolved control mechanisms, also known as checkpoint systems, which sense under-replicated or damaged DNA and activate specialized DNA repair machineries. Cells make use of these checkpoints throughout interphase to shield genome integrity before mitosis. Later on, when the cells enter into mitosis, the spindle assembly checkpoint (SAC) is activated and remains active until the chromosomes are properly attached to the spindle apparatus to ensure an equal segregation among daughter cells. All of these processes are tightly interconnected and under strict regulation in the context of the cell division cycle. The chromosomal instability underlying cancer pathogenesis has recently emerged as a major source for understanding the mitotic processes that helps to safeguard genome integrity. Here, we review the special interconnection between the S-phase and mitosis in the presence of under-replicated DNA regions. Furthermore, we discuss what is known about the DNA damage response activated in mitosis that preserves chromosomal integrity.

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Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements

Cited by 126 publications

References 79 publications

Mechanisms Generating Cancer Genome Complexity From A Single Cell Division Error

Mechanisms Generating Cancer Genome Complexity From A Single Cell Division Error

Under-Replicated DNA: The Byproduct of Large Genomes?

Working on Genomic Stability: From the S-Phase to Mitosis

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