DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis

Dasika, Gopal K.; Lin, Suh Chin J; Zhao, Song; Sung, Patrick; Tomkinson, Alan E.; Lee, Eva Y.-H.P.

doi:10.1038/sj.onc.1203283

Cited by 393 publications

(287 citation statements)

References 193 publications

(227 reference statements)

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“…In wtp53-carrying cells, ADR-induced DNA damage is known to block both G1-S and G2-M transition while direct p53 inactivation results in complete G1 depletion. 28 In murine and human wt53-carrying cells, we showed that the impairment of the ERK2 cleavage by caspase inhibitors interfered with the ADR-induced G1 arrest, slowing down the exit from the cell cycle and determining a partial depletion of the G1 phase. These results indicate that the ERK2 cleavage participates in the p53-mediated mechanisms of G1 arrest.…”

Section: Erk2 Cleavage Is Required For P53 To Inhibit Cell Proliferationmentioning

confidence: 92%

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Marchetti

Cecchinelli²,

D'Angelo³

et al. 2004

Cell Death Differ

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Stimulation of the Ras/MAPK cascade can either activate p53 and promote replicative senescence and apoptosis, or degrade p53 and promote cell survival. Here we show that p53 can directly counteract the Ras/MAPK signaling by inactivating ERK2/MAPK. This inactivation is due to a caspase cleavage of the ERK2 protein and contributes to p53-mediated growth arrest. We found that in Ras-transformed cells, growth arrest induced by p53, but not p21 Waf1 , is associated with a strong reduction in ERK2 activity, phosphorylation, and protein half-life, and with the appearance of caspase activity. Likewise, DNA damage-induced cell cycle arrest correlates with p53-dependent ERK2 downregulation and caspase activation. Furthermore, caspase inhibitors or expression of a caspase-resistant ERK2 mutant interfere with ERK2 cleavage and restore proliferation in the presence of p53 activation, indicating that caspase-mediated ERK2 degradation contributes to p53-induced growth arrest. These findings strongly point to ERK2 as a novel p53 target in growth suppression.

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Section: Erk2 Cleavage Is Required For P53 To Inhibit Cell Proliferationmentioning

confidence: 92%

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Marchetti

Cecchinelli²,

D'Angelo³

et al. 2004

Cell Death Differ

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“…DNA damage checkpoints control both the length of the cell cycle phase and the activation of DNA repair pathways, and movement of DNA repair proteins to the sites of DNA damage, thus helping to integrate DNA repair with cell cycle progression. 39,40 Disassociation of the checkpoints and DNA repair mechanisms can lead to apoptosis. [41][42][43][44] Reports from several laboratories, including ours, have shown that BCR/ABL-positive cells display pronounced G 2 /M delay in response to various chemotherapeutics, which seems to be an essential component in the resistance to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

ATR-Chk1 Axis Protects BCR/ABL Leukemia Cells from the Lethal Effect of DNA Double-Strand Breaks

Nieborowska‐Skorska

Stokłosa²,

Datta³

et al. 2006

Cell Cycle

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BCR/ABL-positive leukemia cells accumulated more replication-dependent DNA doublestrand breaks (DSBs) than normal counterparts after treatment with cisplatin and mitomycin C (MMC, as assessed by pulse field gel electrophoresis (PFGE) and neutral comet assay. In addition, leukemia cells could repair these lesions more efficiently than normal cells and eventually survive genotoxic treatment. Elevated levels of drug-induced DSBs in leukemia cells were associated with higher activity of ATR kinase, and enhanced phosphorylation of histone H2AX on serine 139 (γ-H2AX). γ-H2AX eventually started to disappear in BCR/ABL cells, while continued to increase in parental cells. In addition, the expression and ATR-mediated phosphorylation of Chk1 kinase on serine 345 were often more abundant in BCR/ ABL-positive leukemia cells than normal counterparts after genotoxic treatment. Inhibition of ATR kinase by caffeine but not Chk1 kinase by indolocarbazole inhibitor, SB218078 sensitized BCR/ABL leukemia cells to MMC in a short-term survival assay. Nevertheless, both caffeine and SB218078 enhanced the genotoxic effect of MMC in a long-term clonogenic assay. This effect was associated with the abrogation of transient accumulation of leukemia cells in S and G 2 /M cell cycle phases after drug treatment. In conclusion, ATR -Chk1 axis was strongly activated in BCR/ABL-positive cells and contributed to the resistance to DNA cross-linking agents causing numerous replication-dependent DSBs.

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“…The second is a Tdp1-independent, checkpointdependent pathway involving the Rad9 human homologues in the checkpoint response and the removal of damage by the three parallel functioning endonucleases. Even though there is redundancy in the repair of Top1-mediated DNA damage, it may not be critical to the clinical relevance of Tdp1 inhibition, since it is well established that deficiencies in checkpoint mechanisms are a common feature in cancer cells [71]. For example, if cancer-related checkpoint inactivation arises, then Tdp1 becomes the principle source for the removal of Top1-mediated DNA damage (Fig.…”

Section: Rationale For Targeting Tdp1 For Cancer Therapymentioning

confidence: 99%

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Dexheimer¹,

Antony²,

Marchand³

et al. 2008

ACAMC

144

203

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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a recently discovered enzyme that catalyzes the hydrolysis of 3′-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3′-end DNA alterations including 3′-phosphoglycolates and 3′-abasic sites indicating it may function as a general 3′-DNA phosphodiesterase and repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human TDP1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy.

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DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis

Cited by 393 publications

References 193 publications

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

ATR-Chk1 Axis Protects BCR/ABL Leukemia Cells from the Lethal Effect of DNA Double-Strand Breaks

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

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