Degradation of chromosomal DNA during apoptosis

Nagata, Shinji; Nagase, Hiroko; Kawane, Kohki; Mukae, Naomi; Fukuyama, Hidehiro

doi:10.1038/sj.cdd.4401161

Cited by 395 publications

(298 citation statements)

References 107 publications

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“…Since chromosome fragmentation is also known to occur during programmed cell death (Nagata et al, 2003), we examined if cells treated with WEE1i showed signs of apoptosis. Western-blot analysis of Caspase 3 and PARP integrity showed no evidence for their proteolytic cleavage within the timeline of chromosomes pulverization ( Figure S3D, data not shown).…”

Section: Dna Fragmentation Upon Wee1 Inhibition Is Not Caused By Rpa mentioning

confidence: 99%

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: Dna Fragmentation Upon Wee1 Inhibition Is Not Caused By Rpa mentioning

confidence: 99%

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

et al. 2016

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“…Nuclear degradation during UV-induced apoptosis is marked by internucleosomal DNA cleavage executed by caspaseactivated DNAse (CAD). 31,32 Defects in nuclear degradation during epidermal cornification were not reported in CADdeficient mice. 31 The nucleus is not completely degraded during apoptosis, as nuclear fragments are detectable in the apoptotic bodies that are cleared by uptake by other cells.…”

Section: Nuclear Eventsmentioning

confidence: 99%

“…31,32 Defects in nuclear degradation during epidermal cornification were not reported in CADdeficient mice. 31 The nucleus is not completely degraded during apoptosis, as nuclear fragments are detectable in the apoptotic bodies that are cleared by uptake by other cells. The DNA is further broken down after engulfment.…”

Section: Nuclear Eventsmentioning

confidence: 99%

Death penalty for keratinocytes: apoptosis versus cornification

et al. 2005

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Homeostasis implies a balance between cell growth and cell death. This balance is essential for the development and maintenance of multicellular organisms. Homeostasis is controlled by several mechanisms including apoptosis, a process by which cells condemned to death are completely eliminated. However, in some cases, total destruction and removal of dead cells is not desirable, as when they fulfil a specific function such as formation of the skin barrier provided by corneocytes, also known as terminally differentiated keratinocytes. In this case, programmed cell death results in accumulation of functional cell corpses. Previously, this process has been associated with apoptotic cell death. In this overview, we discuss differences and similarities in the molecular regulation of epidermal programmed cell death and apoptosis. We conclude that despite earlier confusion, apoptosis and cornification occur through distinct molecular pathways, and that possibly antiapoptotic mechanisms are implicated in the terminal differentiation of keratinocytes.

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“…8 Recombinant mouse AIF can induce purified nuclei to undergo chromatin condensation and 'largescale' DNA fragmentation (to B50 kBp), yet has little or no effect on naked DNA or heat-inactived (561C, 30 min) nuclei, indicating that it has to interact with (an)other protein(s) to cause DNA degradation. 1 In contrast, the oligonucleosomal 'ladder type' of DNA fragmentation is mostly mediated by caspase-activated DNAse, lysosomal DNAse II, 9 as well as endonuclease G, another mitochondrial protein that translocates to the nucleus upon apoptosis induction. 10 In C. elegans, AIF has been shown to interact with endonuclease G, both in genetic and in biochemical terms.…”

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confidence: 99%