DNA-Damage-Independent Checkpoints: Yeast and Higher Eukaryotes

Smith, Adrian; Giménez-Abián, Juan F.; Clarke, Duncan J.

doi:10.4161/cc.1.1.96

Cited by 21 publications

(15 citation statements)

References 169 publications

(240 reference statements)

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“…In the presence of drugs such as nocodazole or taxol, wild-type cells were found to arrest in prophase, whereas Chfr-deficient cells progressed into metaphase. This checkpoint is distinct from the mitotic spindle checkpoint involving Mad and Bub proteins that functions to delay the metaphase-to-anaphase transition in the presence of unattached kinetochores (5,7,31,33).…”

mentioning

confidence: 99%

Deficiency in SNM1 Abolishes an Early Mitotic Checkpoint Induced by Spindle Stress

Akhter¹,

Richie²,

Deng³

et al. 2004

Molecular and Cellular Biology

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Spindle poisons represent an important class of anticancer drugs that act by interfering with microtubule polymerization and dynamics and thereby induce mitotic checkpoints and apoptosis. Here we show that mammalian SNM1 functions in an early mitotic stress checkpoint that is distinct from the well-characterized spindle checkpoint that regulates the metaphase-to-anaphase transition. Specifically, we found that compared to wild-type cells, Snm1-deficient mouse embryonic fibroblasts exposed to spindle poisons exhibited elevated levels of micronucleus formation, decreased mitotic delay, a failure to arrest in mitosis prior to chromosome condensation, supernumerary centrosomes, and decreased viability. In addition, we show that both Snm1 and 53BP1, previously shown to interact, coimmunoprecipitate with components of the anaphase-promoting complex (APC)/cyclosome. These findings suggest that Snm1 is a component of a mitotic stress checkpoint that negatively targets the APC prior to chromosome condensation.

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mentioning

confidence: 99%

Deficiency in SNM1 Abolishes an Early Mitotic Checkpoint Induced by Spindle Stress

Akhter¹,

Richie²,

Deng³

et al. 2004

Molecular and Cellular Biology

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“…In mitosis the most extensively characterized checkpoint is the spindle assembly checkpoint, which inhibits the metaphase to anaphase transition until microtubules are fully attached to kinetechores and chromosomes, are aligned at the metaphase plate. [1][2][3][4] An intact spindle checkpoint is required for cellular proliferation, and its complete inactivation results in cellular and embryonic lethality, whereas, partial inactivation can lead to genomic instability and cancer. [5][6][7] Although not as well characterized, a mitotic checkpoint that occurs in early mitosis during prophase in response to spindle stress has also been described.…”

Section: Introductionmentioning

confidence: 99%

SNM1B/Apollo interacts with Astrin and is required for the prophase cell cycle checkpoint

et al. 2009

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Previously, we have shown that SNM1A is a multifunctional gene involved in both the DNA damage response and in an early mitotic checkpoint in response to spindle stress. Another member of the SNM1 gene family, SNM1B/Apollo, has been shown to have roles in both the response to DNA interstrand cross-linking agents and in telomere protection during S phase. Here, we demonstrate a novel role for SNM1B/Apollo in mitosis in response to spindle stress. SNM1B-deficient cells exhibit a defect in the prophase checkpoint. Loss of the prophase checkpoint induces an extended mitotic delay, which is due to prolonged activation of the spindle checkpoint. In addition, we show that SNM1B/Apollo interacts with the essential microtubule binding protein Astrin. SNM1B/ Apollo interacts with Astrin through its conserved metallo-β-lactamase domain, and disruption of this interaction by point mutations results in a deficient prophase checkpoint. These findings suggest that SNM1B/Apollo and Astrin function together to enforce the prophase checkpoint in response to spindle stress.

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“…However, a G2 checkpoint can be activated by parallel pathways (Passalaris et al, 1999;Chan et al, 2000) including DNA damage-independent pathways (Smith et al, 2002), and some p53-deficient cells might be arrested in G2. Then, induction of G2 arrest by low levels of DNA damage may protect some cancer cells with mutant p53 from PTX-mediated death.…”

Section: Introductionmentioning

confidence: 99%

Sequential activation and inactivation of G2 checkpoints for selective killing of p53-deficient cells by microtubule-active drugs

Blagosklonny

2002

Oncogene

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By inducing p53-dependent G2 arrest, the pretreatment with low concentrations of DNA damaging drugs (e.g., doxorubicin, DOX) can prevent cell death caused by microtubule-active drugs (e.g., paclitaxel, PTX), thus potentially permitting selective killing of p53-deficient cancer cells. However, DOX still protects a subset of tumor cell lines lacking wt p53 (HL60 and Jurkat leukemia cells), thus limiting the utility of protection of cells with wt p53 (e.g., normal cells). The present work overcomes this obstacle by adding an abrogator of p53-independent checkpoint (e.g., UCN-01) to the DOX-PTX sequence. By inhibiting a p53-independent pathway, UCN-01 overrode DOX-induced G2 arrest and instead induced G1 arrest in HL60 and Jurkat, thus propelling these p53-deficient cells from G2 to G1. Once they entered mitosis, cells were killed by PTX. Induction of G2 arrest with sequential abrogation of a p53-independent checkpoint allows pharmacological manipulation of Raf-1/Bcl-2 hyperphosphorylation, PARP and Rb cleavage and cell death caused by PTX in p53-deficient cells. Unlike previous approaches, this strategy is intended to increase selectivity, not the cytotoxicity of PTX. This rational sequence of agents that induces p53-dependent and abrogates p53-independent arrest represents a cancerselective strategy for treatment of p53-deficient tumors.

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DNA-Damage-Independent Checkpoints: Yeast and Higher Eukaryotes

Cited by 21 publications

References 169 publications

Deficiency in SNM1 Abolishes an Early Mitotic Checkpoint Induced by Spindle Stress

Deficiency in SNM1 Abolishes an Early Mitotic Checkpoint Induced by Spindle Stress

SNM1B/Apollo interacts with Astrin and is required for the prophase cell cycle checkpoint

Sequential activation and inactivation of G2 checkpoints for selective killing of p53-deficient cells by microtubule-active drugs

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