Replication stress activates DNA repair synthesis in mitosis

Minocherhomji, Sheroy; Ying, Songmin; Bjerregaard, Victoria A.; Bursomanno, Sara; Aleliunaite, Aiste; Wu, Wei; Mankouri, Hocine W; Shen, Huahao; Liu, Ying; Hickson, Ian D.

doi:10.1038/nature16139

Cited by 490 publications

(682 citation statements)

References 30 publications

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“…In agreement with recent reports (Guervilly et al, 2015;Minocherhomji et al, 2015), we found that SLX4 depletion strongly impaired MUS81 recruitment to subnuclear foci during mitosis ( Figure 1G and H). Accordingly, SLX4 depletion caused a 10-fold decrease in MUS81 recruitment to TOPBP1 foci ( Figure 1I).…”

Section: Slx4 Controls the Association Of Multiple Mus81 Molecules Ansupporting

confidence: 94%

A Mechanism for Controlled Breakage of Under-replicated Chromosomes during Mitosis

et al. 2016

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While DNA replication and mitosis occur in a sequential manner, precisely how cells maintain their temporal separation and order remains elusive. Here, we unveil a double-negative feedback loop between replication intermediates and an M-phase-specific structure-selective endonuclease, MUS81-SLX4, which renders DNA replication and mitosis mutually exclusive. MUS81 nuclease is constitutively active throughout the cell cycle but requires association with SLX4 for efficient substrate targeting. To preclude toxic processing of replicating chromosomes, WEE1 kinase restrains CDK1 and PLK1-mediated MUS81-SLX4 assembly during S phase. Accordingly, WEE1 inhibition triggers widespread nucleolytic breakage of replication intermediates, halting DNA replication and leading to chromosome pulverization. Unexpectedly, premature entry into mitosis-licensed by unrestrained CDK1 activity during S phaserequires MUS81-SLX4, which inhibits DNA replication. This suggests that ongoing replication assists WEE1 in delaying entry into M phase and, indirectly, in preventing MUS81-SLX4 assembly. Conversely, MUS81-SLX4 activation during mitosis promotes targeted resolution of persistent replication intermediates, which safeguards chromosome segregation. Unexpectedly, premature entry into mitosis -licensed by unrestrained CDK1 activity during S-phase-requires MUS81-SLX4, which inhibits DNA replication. This suggests that ongoing replication assists WEE1 in delaying entry into M-phase and, indirectly, in preventing MUS81-SLX4 assembly. Conversely, MUS81-SLX4 activation during mitosis promotes targeted resolution of persistent replication intermediates, which safeguards chromosome segregation.3

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Section: Slx4 Controls the Association Of Multiple Mus81 Molecules Ansupporting

confidence: 94%

A Mechanism for Controlled Breakage of Under-replicated Chromosomes during Mitosis

et al. 2016

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“…During early mitosis in mammalian cells, unreplicated DNA can be processed by the Mus81 endonuclease complex, and this leads to DNA synthesis and promotes completion of replication (22). Another solution has been proposed by Moreno et al (20), who showed that regions that fail to complete replication by anaphase are associated in the following G1 with stretches of single-stranded DNA but not double-strand breaks, suggesting that a combination of helicases and topoisomerases can resolve incompletely replicated structures in mitosis and allow the resulting singlestranded gaps to be filled in the following cell cycle.…”

Section: Discussionmentioning

confidence: 99%

SIR2 suppresses replication gaps and genome instability by balancing replication between repetitive and unique sequences

Foss

Lao

Dalrymple

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Replication gaps that persist into mitosis likely represent important threats to genome stability, but experimental identification of these gaps has proved challenging. We have developed a technique that allows us to explore the dynamics by which genome replication is completed before mitosis. Using this approach, we demonstrate that excessive allocation of replication resources to origins within repetitive regions, induced by SIR2 deletion, leads to persistent replication gaps and genome instability. Conversely, the weakening of replication origins in repetitive regions suppresses these gaps. Given known age-and cancer-associated changes in chromatin accessibility at repetitive sequences, we suggest that replication gaps resulting from misallocation of replication resources underlie age-and disease-associated genome instability.SIR2 | DNA replication | repetitive sequences | replication gaps | ribosomal DNA S taggered initiation of DNA replication, which is common across eukaryotes from fungi to humans, means that, at any given time, in S phase, only a fraction of replication origins is activated. In recent years, a model has emerged to explain this pattern of DNA replication (1, 2). This model assumes that the pool of initiation factors required to fire licensed origins in S phase is limited, and therefore sufficient to fire only a subset of licensed origins at any given time. Licensed origins differ in their ability to recruit factors required for firing, so origins with higher affinity or accessibility fire earlier than those with lower affinity or accessibility. After activating the initial set of origins, firing factors are released, enabling the next set of origins to fire. This results in successive waves of origin activation. Genome replication eventually finishes when areas with the least accessible origins are replicated.In healthy human cells, the least accessible genomic regions consist of repetitive DNA, which represents about half of the genome and tends to be compacted into heterochromatin. However, recent studies suggest widespread opening of hetrochromatin during carcinogenesis and aging (3-5). Such reorganization of chromatin would expose a new suite of origins within repetitive DNA that could potentially compete initiation factors away from unique portions of the genome, thereby disrupting the normal genome-wide hierarchy of replication timing. Increased origin activity within repetitive DNA could thus compromise replication elsewhere in the genome. Given the limited pool of initiation factors, we propose that an increase in density of active origins within repetitive regions could result in a decreased density of such origins in unique regions of the genome, which, when combined with the stochastic nature of origin firing, may occasionally result in replication gaps, i.e., unique regions of the genome that are unable to complete replication before mitosis. This so-called "Random Replication Gap Problem" (RRGP) is the subject of long-standing speculation, but such gaps have never been experim...

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“…Curiously, there is evidence within animal systems that repair and monitoring mechanisms are active near the end and after S-phase. 13 However, there are no known reports of such latent DNA replication in plant systems, especially within a stress induced system such as the woundhealing model of potato tuber where there are several days separating DNA synthesis and initiation of related cell division (Fig 1 and Table 1). A study similar to that of Minocherhomji et al 13 on undifferentiated potato tuber cells may be hampered by the need to culture and manipulate the responding cells (in vivo) where typical epigenetic effects severely complicate the ability to induce responses that simulate in situ processes like that demonstrated with potato tissue.…”

Section: Biological Processes Associated With Closing Layer Formationmentioning

confidence: 99%

“…13 However, there are no known reports of such latent DNA replication in plant systems, especially within a stress induced system such as the woundhealing model of potato tuber where there are several days separating DNA synthesis and initiation of related cell division (Fig 1 and Table 1). A study similar to that of Minocherhomji et al 13 on undifferentiated potato tuber cells may be hampered by the need to culture and manipulate the responding cells (in vivo) where typical epigenetic effects severely complicate the ability to induce responses that simulate in situ processes like that demonstrated with potato tissue. Notably, all EdU labeled entities, indicating DNA synthesis in process, labeled positively with 4 0 , 6-diamindino-2-phenylindole (DAPI) before, during, and after induction into S-phase confirming identity as nuclei in these wound responding tissues.…”

Section: Biological Processes Associated With Closing Layer Formationmentioning

confidence: 99%

Biological differences that distinguish the 2 major stages of wound healing in potato tubers

Lulai

Campbell

Fugate

et al. 2016

Plant Signaling & Behavior

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The two stages of potato tuber wound healing, closing layer formation (CLF) and wound periderm formation (WPF), have critical biological differences. The first stage, CLF, involves early induction of DNA synthesis and nuclear division in the absence of cell division. The transition phase from CLF to the second stage, WPF, is marked by a transient decrease in expression of suberin-specific genes. The second stage involves cell division. Although biologically active cytokinins (CKs) are not present in quantifiable amounts during this stage, the presence of precursor and catabolic products suggest the presence of trace amounts of active CKs that, in conjunction with increased auxin (indole acetic acid), provide necessary signals for meristematic activity. Augmenting these putative trace amounts with exogenous biologically active CK inhibits WPF; this suggests that the CK requirements for meristematic activity are finely controlled and sensitive to extremely low concentrations. Evidence is discussed for separate biological processes and signals that distinguish the 2 stages of wound healing.

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Replication stress activates DNA repair synthesis in mitosis

Cited by 490 publications

References 30 publications

A Mechanism for Controlled Breakage of Under-replicated Chromosomes during Mitosis

A Mechanism for Controlled Breakage of Under-replicated Chromosomes during Mitosis

SIR2 suppresses replication gaps and genome instability by balancing replication between repetitive and unique sequences

Biological differences that distinguish the 2 major stages of wound healing in potato tubers

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