The Drosophila Grp/Chk1 DNA Damage Checkpoint Controls Entry into Anaphase

Royou, Anne; Macias, Hector; Sullivan, William M.

doi:10.1016/j.cub.2005.02.026

Cited by 60 publications

(69 citation statements)

References 31 publications

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“…Indeed, the partial decline in myt1 mutant PH3-labeled cells observed immediately after exposure to ionizing radiation could reflect activation of an otherwise dispensable Wee1-regulated premitotic checkpoint mechanism. The remaining PH3-positive cells that persisted long after irradiation in myt1 mutant discs could be arrested in mitosis by an alternative regulatory mechanism that was responsive to DNA damage (Sanchez et al 1999;Royou et al 2005;Kim and Burke 2008;Musaro et al 2008). Further studies will be needed to clarify the respective roles of dMyt1 and dWee1 in cellular responses to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Drosophila Myt1 Is the Major Cdk1 Inhibitory Kinase for Wing Imaginal Disc Development

Jin¹,

Homola

Tiong

et al. 2008

Genetics

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Mitosis is triggered by activation of Cdk1, a cyclin-dependent kinase. Conserved checkpoint mechanisms normally inhibit Cdk1 by inhibitory phosphorylation during interphase, ensuring that DNA replication and repair is completed before cells begin mitosis. In metazoans, this regulatory mechanism is also used to coordinate cell division with critical developmental processes, such as cell invagination. Two types of Cdk1 inhibitory kinases have been found in metazoans. They differ in subcellular localization and Cdk1 target-site specificity: one (Wee1) being nuclear and the other (Myt1), membrane-associated and cytoplasmic. Drosophila has one representative of each: dMyt1 and dWee1. Although dWee1 and dMyt1 are not essential for zygotic viability, loss of both resulted in synthetic lethality, indicating that they are partially functionally redundant. Bristle defects in myt1 mutant adult flies prompted a phenotypic analysis that revealed cell-cycle defects, ectopic apoptosis, and abnormal responses to ionizing radiation in the myt1 mutant imaginal wing discs that give rise to these mechanosensory organs. Cdk1 inhibitory phosphorylation was also aberrant in these myt1 mutant imaginal wing discs, indicating that dMyt1 serves Cdk1 regulatory functions that are important both for normal cell-cycle progression and for coordinating mitosis with critical developmental processes.

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Section: Discussionmentioning

confidence: 99%

Drosophila Myt1 Is the Major Cdk1 Inhibitory Kinase for Wing Imaginal Disc Development

Jin¹,

Homola

Tiong

et al. 2008

Genetics

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“…These early studies, and many others since, have shown that mitotic DNA damage mediates a slowing of phase progression by activating, or delaying the inactivation, of the SAC. Recent research in a number of species has determined that the incorporation of mitotic DNA damage leads to the activation of SAC component BubR1, which is thought to be vital in the mitotic delay (Royou et al, 2005;Fang et al, 2006;Choi and Lee, 2008). It is generally believed that widespread DNA damage or structural changes to chromatin affect the centromere region, which results in the disruption of kinetochore structure/function (Garber and Rine, 2006).…”

Section: Inactive Sacmentioning

confidence: 99%

“…An alternative mitotic DNA damage checkpoint mechanism was devised from studies in Drosophila embryos in which ATM (Mei-41 in the fly) induction is thought to cause a mitotic delay by stabilising Cyclin A, which prevents anaphase onset (Su and Jaklevic, 2001;Laurencon et al, 2003). It has also been shown in Drosophila embryos that DSBs, away from kinetochore regions, retard mitosis progression through activation of a Chk1 signalling pathway (Royou et al, 2005). Works by Huang et al, have demonstrated that DNA damage in human cells elicits a mitotic exit blockade dependent on BRCA1 and Chk1 (Huang et al, 2005).…”

Section: The Potential Existence Of Dna Damage Mitotic Checkpointsmentioning

confidence: 99%

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

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“…DNA damage does not affect entry into M (NA). The role of grp in regulating progress through M in response to damaged DNA in larvae was published recently (Royou et al, 2005) but not shown in the Table. *Data presented in this paper.…”

Section: Western Blottingmentioning

confidence: 99%

“…A recently published report documents the regulation of metaphase-anaphase transition by checkpoints in response to DNA double-strand breaks in Drosophila larvae (Royou et al, 2005). This checkpoint, first described in embryos, is not limited to the embryo.…”

Section: Metaphase-anaphase Checkpointmentioning

confidence: 99%

Regulation of mitosis in response to damaged or incompletely replicated DNA require different levels of Grapes (DrosophilaChk1)

Purdy

Uyetake

Cordeiro

et al. 2005

Journal of Cell Science

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Checkpoints monitor the state of DNA and can delay or arrest the cell cycle at multiple points including G1-S transition, progress through S phase and G2-M transition. Regulation of progress through mitosis, specifically at the metaphase-anaphase transition, occurs after exposure to ionizing radiation (IR) in Drosophila and budding yeast, but has not been conclusively demonstrated in mammals. Here we report that regulation of metaphase-anaphase transition in Drosophila depends on the magnitude of radiation dose and time in the cell cycle at which radiation is applied, which may explain the apparent differences among experimental systems and offer an explanation as to why this regulation has not been seen in mammalian cells. We further document that mutants in Drosophila Chk1 (Grapes) that are capable of delaying the progress through mitosis in response to IR are incapable of delaying progress through mitosis when DNA synthesis is blocked by mutations in an essential replication factor encoded by double park (Drosophila Cdt1). We conclude that DNA damage and replication checkpoints operating in the same cell cycle at the same developmental stage in Drosophila can exhibit differential requirements for the Chk1 homolog. The converse situation exists in fission yeast where loss of Chk1 is more detrimental to the DNA damage checkpoint than to the DNA replication checkpoint. It remains to be seen which of these two different uses of Chk1 homologs are conserved in mammals. Finally, our results demonstrate that Drosophila provides a unique opportunity to study the regulation of the entry into, and progress through, mitosis by DNA structure checkpoints in metazoa.

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The Drosophila Grp/Chk1 DNA Damage Checkpoint Controls Entry into Anaphase

Cited by 60 publications

References 31 publications

Drosophila Myt1 Is the Major Cdk1 Inhibitory Kinase for Wing Imaginal Disc Development

Drosophila Myt1 Is the Major Cdk1 Inhibitory Kinase for Wing Imaginal Disc Development

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Regulation of mitosis in response to damaged or incompletely replicated DNA require different levels of Grapes (DrosophilaChk1)

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