Conservation of the Chk1 Checkpoint Pathway in Mammals: Linkage of DNA Damage to Cdk Regulation Through Cdc25

Sánchez, Yolanda; Wong, Calvin; Thoma, Richard S.; Richman, Robert A.; Wu, Zijuan; Piwnica‐Worms, Helen; Elledge, Stephen J.

doi:10.1126/science.277.5331.1497

Cited by 1,196 publications

(1,034 citation statements)

References 22 publications

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“…UV damage, 14-3-3 proteins bind to the phosphatase, Cdc25p, thereby inhibiting its ability to dephosphorylate Cdc2, leading to G 1 or G 2 arrest (Peng et al, 1997). A similar mechanism was demonstrated in mammalian cells (Sanchez et al, 1997). Although RAD24 and RAD25 appear to be functionally redundant, Rad25p has only marginal effects on resistance to UV resistance (Ford et al, 1994).…”

Section: Introductionmentioning

confidence: 85%

The Candida albicans 14‐3‐3 gene, BMH1, is essential for growth

Cognetti

Davis

Sturtevant

2001

Yeast

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The 14-3-3 proteins are a family of conserved small acidic proteins that have been implicated in playing major roles in a wide variety of signalling cascades. In Saccharomyces cerevisiae, the 14-3-3 genes (BMH1 and BMH2) are essential for normal pseudohyphal induction and normal bud cell development. The Bmh proteins function in the cAMPdependent RAS/MAPK and rapamycin-sensitive signalling cascades. Deletion of only one BMH gene demonstrates no phenotypic differences under normal growth conditions. Strains deleted of both BMH1 and BMH2 are either non-viable or demonstrate sensitivity to environmental stresses. In Schizosaccharomyces pombe, the BMH homologues (RAD24 and RAD25) are essential for cell cycle control after DNA damage and deletion of both genes renders the cell inviable. The 14-3-3 gene in Candida albicans (BMH1) was identified using a novel adherence assay and differential display RT-PCR. Unlike other yeasts, C. albicans has only one 14-3-3 gene (BMH1). It was not possible to construct double knockouts by routine methods. These results suggested that the C. albicans BMH1 gene is essential. The essentiality of C. albicans BMH1 was confirmed by a PCR disruption technique. The C. albicans bmh1D/BMH1 heterozygotes exhibit growth and morphogenetic defects. Therefore, the BMH1 gene in C. albicans (Accession No. AF038154) is an excellent candidate to improve our understanding of the coordinate regulation of cell cycle and morphogenesis.

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Section: Introductionmentioning

confidence: 85%

The Candida albicans 14‐3‐3 gene, BMH1, is essential for growth

Cognetti

Davis

Sturtevant

2001

Yeast

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“…Mitosis onset is prevented in response to DNA damage through the stabilisation of the inhibitory phosphorylation on Cdk1-Cyclin B (Dasso and Newpot, 1990;Jin et al, 1996). Activated ATM and ATR induce Chk1 and Chk2, which initiates Cdc25 inhibition and/or degradation (Matsuoka et al, 1998;Sanchez et al, 1997;Kastan and Bartek, 2004). For example, in fission yeast, Chk1 kinase phosphorylation of Cdc25C at Ser216 enables 14-3-3 proteins to bind, which leads to nuclear displacement of Cdc25C, preventing dephosphorylation of Cdk1-Cyclin B1 (Peng et al, 1997).…”

Section: G2/m Phase Transition Checkpointmentioning

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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“…Appearance of phosphorylated upper bands of Cdc25C, Myt 1 and Bcl-2 are hallmarks of the presence of mitotic cells (Sanchez et al, 1997;Ling et al, 1998). Although nocodazole treatment for 12 h gave rise to the retarded upper bands of Cdc25C, Myt 1 and Bcl-2 in rapidly growing Jurkat cells, pre-and simultaneous treatment with 50 nM doxorubicin completely eliminated their upper retardation.…”

Section: Treatment With Geldanamycin Depleted Chk1 Proteinmentioning

confidence: 99%

“…Chk1 plays the central role in DNA damage-induced G 2 arrest by maintaining Cdc25C in the phosphorylated inactive form, which suppresses Cdc2 activation (Elledge, 1996;Peng et al, 1997;Sanchez et al, 1997;Weinert, 1997;Bulavin et al, 2003). Caffeine has been shown to abrogate DNA damage-induced G 2 arrest by inhibiting Ataxia telangiectasia mutated (ATM) and ATM-related (ATR) kinases, which situated upstream of Chk1 in the DNA damage checkpoint pathway (Fan et al, 1995;Powell et al, 1995;Russell et al, 1995;Yao et al, 1996;Sarkaria et al, 1999).…”

Section: Introductionmentioning

confidence: 99%